APOE

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0120020 cholesterol transfer activity	IBA GO_REF:0000033	ACCEPT	Summary: APOE cholesterol transfer activity is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0042627 chylomicron	IBA GO_REF:0000033	ACCEPT	Summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005543 phospholipid binding	IBA GO_REF:0000033	ACCEPT	Summary: APOE phospholipid binding is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0008203 cholesterol metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0033344 cholesterol efflux	IBA GO_REF:0000033	ACCEPT	Summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0033700 phospholipid efflux	IBA GO_REF:0000033	ACCEPT	Summary: phospholipid efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0034361 very-low-density lipoprotein particle	IBA GO_REF:0000033	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034362 low-density lipoprotein particle	IBA GO_REF:0000033	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IBA GO_REF:0000033	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0055090 acylglycerol homeostasis	IBA GO_REF:0000033	ACCEPT	Summary: acylglycerol homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0060228 phosphatidylcholine-sterol O-acyltransferase activator activity	IBA GO_REF:0000033	ACCEPT	Summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific activity within its lipoprotein remodeling role. Reason: LCAT activation is a mechanistically specific APOE molecular function tied to cholesterol esterification and lipoprotein remodeling. Supporting Evidence: PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:1903561 extracellular vesicle	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: APOE localization to extracellular vesicle is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005771 multivesicular body	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: APOE localization to multivesicular body is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0006869 lipid transport	IEA GO_REF:0000002	ACCEPT	Summary: lipid transport is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0008289 lipid binding	IEA GO_REF:0000002	ACCEPT	Summary: APOE lipid binding is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0042157 lipoprotein metabolic process	IEA GO_REF:0000002	ACCEPT	Summary: lipoprotein metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0098869 cellular oxidant detoxification	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: APOE-associated cellular oxidant detoxification is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance.
GO:1903561 extracellular vesicle	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: APOE localization to extracellular vesicle is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0005515 protein binding	IPI PMID:12950167 Domains of apoE required for binding to apoE receptor 2 and ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:15182176 Two apolipoprotein E mimetic peptides, ApoE(130-149) and Apo...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:15615705 CLAC binds to amyloid beta peptides through the positively c...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:17116874 Blocking the apolipoprotein E/amyloid-beta interaction as a ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:19758344 Haptoglobin binds the antiatherogenic protein apolipoprotein...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:20030366 Decoding of lipoprotein-receptor interactions: properties of...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:21163940 Interactome mapping suggests new mechanistic details underly...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:21593558 The impact of a novel apolipoprotein E and amyloid-β protein...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:22528093 Search for amyloid-binding proteins by affinity chromatograp...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:24447298 LDL receptor/lipoprotein recognition: endosomal weakening of...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:25122793 Apolipoprotein E likely contributes to a maturation step of ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:26468283 Complement Factor H Binds to Human Serum Apolipoprotein E an...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:26921451 Effects of different isoforms of apoE on aggregation of the ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:28887769 α-Synuclein Interacts with Lipoproteins in Plasma.	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:29507344 Effect of human very low-density lipoproteins on cardiotroph...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:30341064 High-affinity interactions and signal transduction between A...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:31270237 α-synuclein-lipoprotein interactions and elevated ApoE level...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:7566652 ApoE3 binding to tau tandem repeat I is abolished by tau ser...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0010629 negative regulation of gene expression	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: negative regulation of gene expression is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0010875 positive regulation of cholesterol efflux	IEA GO_REF:0000107	ACCEPT	Summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0010877 lipid transport involved in lipid storage	IEA GO_REF:0000107	ACCEPT	Summary: lipid transport involved in lipid storage is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0010976 positive regulation of neuron projection development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0032438 melanosome organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: melanosome organization is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0034362 low-density lipoprotein particle	IEA GO_REF:0000120	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034372 very-low-density lipoprotein particle remodeling	IEA GO_REF:0000107	ACCEPT	Summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0034374 low-density lipoprotein particle remodeling	IEA GO_REF:0000107	ACCEPT	Summary: low-density lipoprotein particle remodeling is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0042981 regulation of apoptotic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: regulation of apoptotic process is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0043395 heparan sulfate proteoglycan binding	IEA GO_REF:0000107	ACCEPT	Summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0045088 regulation of innate immune response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: regulation of innate immune response is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0050728 negative regulation of inflammatory response	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: negative regulation of inflammatory response is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0050807 regulation of synapse organization	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including regulation of synapse organization, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0060228 phosphatidylcholine-sterol O-acyltransferase activator activity	IEA GO_REF:0000107	ACCEPT	Summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific activity within its lipoprotein remodeling role. Reason: LCAT activation is a mechanistically specific APOE molecular function tied to cholesterol esterification and lipoprotein remodeling. Supporting Evidence: PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0070328 triglyceride homeostasis	IEA GO_REF:0000107	ACCEPT	Summary: triglyceride homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0071813 lipoprotein particle binding	IEA GO_REF:0000107	ACCEPT	Summary: APOE lipoprotein particle binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0071830 triglyceride-rich lipoprotein particle clearance	IEA GO_REF:0000107	ACCEPT	Summary: triglyceride-rich lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0090205 positive regulation of cholesterol metabolic process	IEA GO_REF:0000107	ACCEPT	Summary: positive regulation of cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0097006 regulation of plasma lipoprotein particle levels	IEA GO_REF:0000107	ACCEPT	Summary: regulation of plasma lipoprotein particle levels is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0098978 glutamatergic synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0120020 cholesterol transfer activity	IEA GO_REF:0000107	ACCEPT	Summary: APOE cholesterol transfer activity is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:1900223 positive regulation of amyloid-beta clearance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid-beta clearance, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:1905907 negative regulation of amyloid fibril formation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid fibril formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0001523 retinoid metabolic process	TAS Reactome:R-HSA-975634	KEEP AS NON CORE	Summary: retinoid metabolic process is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005576 extracellular region	EXP PMID:2498325 Glycosylation of human apolipoprotein E. The carbohydrate at...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	EXP PMID:30333625 LILRB4 signalling in leukaemia cells mediates T cell suppres...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:1903561 extracellular vesicle	EXP PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	KEEP AS NON CORE	Summary: APOE localization to extracellular vesicle is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0050750 low-density lipoprotein particle receptor binding	TAS Reactome:R-HSA-2423785	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0005576 extracellular region	HDA PMID:27559042 Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0010642 negative regulation of platelet-derived growth factor receptor signaling pathway	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: negative regulation of platelet-derived growth factor receptor signaling pathway is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:9685360 Taken together, these results suggest that apoE has cytostatic functions in the vessel wall
GO:0043409 negative regulation of MAPK cascade	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: negative regulation of MAPK cascade is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:9685360 Taken together, these results suggest that apoE has cytostatic functions in the vessel wall
GO:0034360 chylomicron remnant	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: APOE is appropriately localized to chylomicron remnant as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0050728 negative regulation of inflammatory response	IDA PMID:8995232 Apolipoprotein E inhibits platelet aggregation through the L...	KEEP AS NON CORE	Summary: negative regulation of inflammatory response is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0140077 positive regulation of lipoprotein transport	IDA PMID:8300609 Secretion-capture role for apolipoprotein E in remnant lipop...	ACCEPT	Summary: positive regulation of lipoprotein transport is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0048018 receptor ligand activity	IDA PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,...	KEEP AS NON CORE	Summary: receptor ligand activity is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:27477018 we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2.
GO:0071402 cellular response to lipoprotein particle stimulus	IDA PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,...	KEEP AS NON CORE	Summary: cellular response to lipoprotein particle stimulus is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0043083 synaptic cleft	IEP PMID:22637583 Apolipoprotein E4 effects in Alzheimer's disease are mediate...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including synaptic cleft, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0043083 synaptic cleft	IDA PMID:22637583 Apolipoprotein E4 effects in Alzheimer's disease are mediate...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including synaptic cleft, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0098978 glutamatergic synapse	IEP PMID:22637583 Apolipoprotein E4 effects in Alzheimer's disease are mediate...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0098978 glutamatergic synapse	IDA PMID:22637583 Apolipoprotein E4 effects in Alzheimer's disease are mediate...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0038060 nitric oxide-cGMP-mediated signaling	IDA PMID:8995232 Apolipoprotein E inhibits platelet aggregation through the L...	KEEP AS NON CORE	Summary: nitric oxide-cGMP-mediated signaling is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:8995232 We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway.
GO:0045429 positive regulation of nitric oxide biosynthetic process	IDA PMID:8995232 Apolipoprotein E inhibits platelet aggregation through the L...	KEEP AS NON CORE	Summary: positive regulation of nitric oxide biosynthetic process is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:8995232 We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway.
GO:0034382 chylomicron remnant clearance	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034447 very-low-density lipoprotein particle clearance	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0043395 heparan sulfate proteoglycan binding	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0045807 positive regulation of endocytosis	IDA PMID:7683668 Role of heparan sulfate proteoglycans in the binding and upt...	ACCEPT	Summary: positive regulation of endocytosis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing lipoproteins and remnants. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0042803 protein homodimerization activity	IPI PMID:8089103 Isoform-specific binding of apolipoprotein E to beta-amyloid...	KEEP AS NON CORE	Summary: protein homodimerization activity reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0042803 protein homodimerization activity	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	KEEP AS NON CORE	Summary: protein homodimerization activity reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0097487 multivesicular body, internal vesicle	IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	KEEP AS NON CORE	Summary: APOE localization to multivesicular body, internal vesicle is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0005515 protein binding	IPI PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0032438 melanosome organization	IMP PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	KEEP AS NON CORE	Summary: melanosome organization is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0042470 melanosome	IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	KEEP AS NON CORE	Summary: melanosome is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0070062 extracellular exosome	IDA PMID:26387950 Apolipoprotein E Regulates Amyloid Formation within Endosome...	KEEP AS NON CORE	Summary: APOE localization to extracellular exosome is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0019899 enzyme binding	IPI PMID:15654758 Apolipoprotein E is the major physiological activator of lec...	MARK AS OVER ANNOTATED	Summary: Generic enzyme binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0090205 positive regulation of cholesterol metabolic process	IDA PMID:15654758 Apolipoprotein E is the major physiological activator of lec...	ACCEPT	Summary: positive regulation of cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0097113 AMPA glutamate receptor clustering	IDA PMID:24328732 ApoE4 delays dendritic spine formation during neuron develop...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including AMPA glutamate receptor clustering, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0097114 NMDA glutamate receptor clustering	IDA PMID:24328732 ApoE4 delays dendritic spine formation during neuron develop...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including NMDA glutamate receptor clustering, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0090090 negative regulation of canonical Wnt signaling pathway	IGI PMID:16805831 Inhibition of the canonical Wnt signaling pathway by apolipo...	KEEP AS NON CORE	Summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0048662 negative regulation of smooth muscle cell proliferation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: negative regulation of smooth muscle cell proliferation is retained as non-core APOE-associated biology pending a deeper reference-specific adjudication. Reason: The annotation is not part of the primary lipid-transport and lipoprotein-clearance function set, but available local evidence was not sufficient to remove it.
GO:0005576 extracellular region	TAS Reactome:R-HSA-976734	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0046983 protein dimerization activity	IPI PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	KEEP AS NON CORE	Summary: protein dimerization activity reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0060999 positive regulation of dendritic spine development	IDA PMID:24328732 ApoE4 delays dendritic spine formation during neuron develop...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of dendritic spine development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:1902952 positive regulation of dendritic spine maintenance	IDA PMID:24328732 ApoE4 delays dendritic spine formation during neuron develop...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of dendritic spine maintenance, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0005102 signaling receptor binding	IPI PMID:27477018 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ,...	KEEP AS NON CORE	Summary: signaling receptor binding is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:27477018 we identified a set of lipoprotein particles (including LDL) and apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2.
GO:0043254 regulation of protein-containing complex assembly	IDA PMID:25207746 The binding of apolipoprotein E to oligomers and fibrils of ...	KEEP AS NON CORE	Summary: regulation of protein-containing complex assembly is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0044877 protein-containing complex binding	IDA PMID:25207746 The binding of apolipoprotein E to oligomers and fibrils of ...	MARK AS OVER ANNOTATED	Summary: Generic protein-containing complex binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0005515 protein binding	IPI PMID:30448281 Soluble LR11 competes with amyloid β in binding to cerebrosp...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:1902991 regulation of amyloid precursor protein catabolic process	IDA PMID:28164773 Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer'...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid precursor protein catabolic process, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:1900223 positive regulation of amyloid-beta clearance	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid-beta clearance, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:1905907 negative regulation of amyloid fibril formation	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid fibril formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0010596 negative regulation of endothelial cell migration	IMP PMID:23142051 Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-de...	KEEP AS NON CORE	Summary: APOE-associated negative regulation of endothelial cell migration is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:9685360 Taken together, these results suggest that apoE has cytostatic functions in the vessel wall
GO:0050709 negative regulation of protein secretion	IMP PMID:27044754 FRMD4A-cytohesin signaling modulates the cellular release of...	KEEP AS NON CORE	Summary: negative regulation of protein secretion is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0031175 neuron projection development	IDA PMID:8939961 Apolipoprotein E-containing high density lipoprotein promote...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0033344 cholesterol efflux	IDA PMID:23620513 ApoE influences amyloid-β (Aβ) clearance despite minimal apo...	ACCEPT	Summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0042158 lipoprotein biosynthetic process	IDA PMID:23620513 ApoE influences amyloid-β (Aβ) clearance despite minimal apo...	ACCEPT	Summary: lipoprotein biosynthetic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid binding, ABCA1-dependent efflux, and LCAT activation. Supporting Evidence: PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:14754908 ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo. PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0043395 heparan sulfate proteoglycan binding	IDA PMID:23676495 Apolipoproteins E and AV mediate lipoprotein clearance by he...	ACCEPT	Summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0071830 triglyceride-rich lipoprotein particle clearance	IMP PMID:23676495 Apolipoproteins E and AV mediate lipoprotein clearance by he...	ACCEPT	Summary: triglyceride-rich lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034382 chylomicron remnant clearance	IDA PMID:1911868 Effects of exogenous apo E-3 and of cholesterol-enriched mea...	ACCEPT	Summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0005576 extracellular region	IDA PMID:8340399 Discrete carboxyl-terminal segments of apolipoprotein E medi...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0031012 extracellular matrix	IDA PMID:9488694 The HepG2 extracellular matrix contains separate heparinase-...	ACCEPT	Summary: APOE is appropriately localized to extracellular matrix as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0042802 identical protein binding	IDA PMID:8340399 Discrete carboxyl-terminal segments of apolipoprotein E medi...	KEEP AS NON CORE	Summary: identical protein binding reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0043395 heparan sulfate proteoglycan binding	IDA PMID:9488694 The HepG2 extracellular matrix contains separate heparinase-...	ACCEPT	Summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0071831 intermediate-density lipoprotein particle clearance	IDA PMID:1917954 Mechanisms of inhibition by apolipoprotein C of apolipoprote...	ACCEPT	Summary: intermediate-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034447 very-low-density lipoprotein particle clearance	IDA PMID:2762297 Low density lipoprotein receptor-related protein mediates up...	ACCEPT	Summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:2280190 Apolipoprotein E distribution among human plasma lipoprotein...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:8071364 Human apolipoprotein E. Role of arginine 61 in mediating the...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034362 low-density lipoprotein particle	IDA PMID:2280190 Apolipoprotein E distribution among human plasma lipoprotein...	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034363 intermediate-density lipoprotein particle	IDA PMID:2280190 Apolipoprotein E distribution among human plasma lipoprotein...	ACCEPT	Summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IDA PMID:2280190 Apolipoprotein E distribution among human plasma lipoprotein...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IDA PMID:8071364 Human apolipoprotein E. Role of arginine 61 in mediating the...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005515 protein binding	IPI PMID:14754908 Molecular interactions between apoE and ABCA1: impact on apo...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0008201 heparin binding	IDA PMID:7635945 Dominant expression of type III hyperlipoproteinemia. Pathop...	ACCEPT	Summary: APOE heparin binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034364 high-density lipoprotein particle	IDA PMID:14754908 Molecular interactions between apoE and ABCA1: impact on apo...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034380 high-density lipoprotein particle assembly	IDA PMID:14754908 Molecular interactions between apoE and ABCA1: impact on apo...	ACCEPT	Summary: high-density lipoprotein particle assembly is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid binding, ABCA1-dependent efflux, and LCAT activation. Supporting Evidence: PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:14754908 ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo. PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0050750 low-density lipoprotein particle receptor binding	IDA PMID:7635945 Dominant expression of type III hyperlipoproteinemia. Pathop...	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0050750 low-density lipoprotein particle receptor binding	IDA PMID:1530612 Site-directed mutagenesis of an apolipoprotein E mutant, apo...	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0045893 positive regulation of DNA-templated transcription	IMP PMID:28111074 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcr...	KEEP AS NON CORE	Summary: positive regulation of DNA-templated transcription is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:28111074 ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
GO:0061136 regulation of proteasomal protein catabolic process	IMP PMID:28111074 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcr...	KEEP AS NON CORE	Summary: regulation of proteasomal protein catabolic process is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:28111074 ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IMP PMID:28111074 ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcr...	KEEP AS NON CORE	Summary: positive regulation of ERK1 and ERK2 cascade is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions. Supporting Evidence: PMID:28111074 ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
GO:0005576 extracellular region	HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	HDA PMID:20551380 Proteomics characterization of extracellular space component...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0010629 negative regulation of gene expression	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: negative regulation of gene expression is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0005576 extracellular region	ISS GO_REF:0000024	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0007616 long-term memory	IGI PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including long-term memory, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0035641 locomotory exploration behavior	IMP PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including locomotory exploration behavior, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0042632 cholesterol homeostasis	IGI PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	ACCEPT	Summary: cholesterol homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0051044 positive regulation of membrane protein ectodomain proteolysis	IGI PMID:25015123 Apolipoprotein E isoform-specific effects on lipoprotein rec...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of membrane protein ectodomain proteolysis, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0051246 regulation of protein metabolic process	IGI PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	KEEP AS NON CORE	Summary: regulation of protein metabolic process is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0061771 response to caloric restriction	IGI PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	KEEP AS NON CORE	Summary: response to caloric restriction is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0090181 regulation of cholesterol metabolic process	IGI PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	ACCEPT	Summary: regulation of cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:2000822 regulation of behavioral fear response	IMP PMID:24412220 Apolipoprotein E-low density lipoprotein receptor interactio...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including regulation of behavioral fear response, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0034365 discoidal high-density lipoprotein particle	TAS PMID:22383525 Low-density lipoprotein receptor represents an apolipoprotei...	ACCEPT	Summary: APOE is appropriately localized to discoidal high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0050750 low-density lipoprotein particle receptor binding	NAS PMID:20005821 Overexpression of low-density lipoprotein receptor in the br...	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:1905908 positive regulation of amyloid fibril formation	TAS PMID:20005821 Overexpression of low-density lipoprotein receptor in the br...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid fibril formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0001540 amyloid-beta binding	IDA PMID:25207746 The binding of apolipoprotein E to oligomers and fibrils of ...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:1905906 regulation of amyloid fibril formation	IDA PMID:25207746 The binding of apolipoprotein E to oligomers and fibrils of ...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid fibril formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0001540 amyloid-beta binding	IPI PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0005198 structural molecule activity	TAS PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	KEEP AS NON CORE	Summary: structural molecule activity reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0006898 receptor-mediated endocytosis	TAS PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: receptor-mediated endocytosis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing lipoproteins and remnants. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034362 low-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034363 intermediate-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:1905908 positive regulation of amyloid fibril formation	TAS PMID:9228033 Interaction of apolipoprotein J-amyloid beta-peptide complex...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid fibril formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:1990777 lipoprotein particle	IDA PMID:22138302 Preferential interactions between ApoE-containing lipoprotei...	ACCEPT	Summary: APOE is appropriately localized to lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0001540 amyloid-beta binding	IPI PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0042982 amyloid precursor protein metabolic process	IDA PMID:21593558 The impact of a novel apolipoprotein E and amyloid-β protein...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid precursor protein metabolic process, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0010976 positive regulation of neuron projection development	IDA PMID:7592957 Stable expression and secretion of apolipoproteins E3 and E4...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0010977 negative regulation of neuron projection development	IDA PMID:7592957 Stable expression and secretion of apolipoproteins E3 and E4...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including negative regulation of neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:1905890 regulation of cellular response to very-low-density lipoprotein particle stimulus	IDA PMID:7592957 Stable expression and secretion of apolipoproteins E3 and E4...	ACCEPT	Summary: regulation of cellular response to very-low-density lipoprotein particle stimulus is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0010976 positive regulation of neuron projection development	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0010976 positive regulation of neuron projection development	IDA PMID:23845000 Isoform-specific effects of apoE on neurite outgrowth in olf...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron projection development, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:1900272 negative regulation of long-term synaptic potentiation	IDA PMID:16273551 Blockade of nicotinic acetylcholine receptors suppresses hip...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including negative regulation of long-term synaptic potentiation, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0005576 extracellular region	IDA PMID:16805831 Inhibition of the canonical Wnt signaling pathway by apolipo...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0051248 negative regulation of protein metabolic process	IGI PMID:16805831 Inhibition of the canonical Wnt signaling pathway by apolipo...	KEEP AS NON CORE	Summary: negative regulation of protein metabolic process is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0090090 negative regulation of canonical Wnt signaling pathway	IDA PMID:16805831 Inhibition of the canonical Wnt signaling pathway by apolipo...	KEEP AS NON CORE	Summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8952289	KEEP AS NON CORE	Summary: endoplasmic reticulum lumen is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034362 low-density lipoprotein particle	IDA PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034363 intermediate-density lipoprotein particle	IDA PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IDA PMID:9211985 Association of human, rat, and rabbit apolipoprotein E with ...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0001540 amyloid-beta binding	IPI PMID:9003062 Characterization of the binding of amyloid-beta peptide to c...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0045807 positive regulation of endocytosis	IDA PMID:8300609 Secretion-capture role for apolipoprotein E in remnant lipop...	ACCEPT	Summary: positive regulation of endocytosis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing lipoproteins and remnants. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0001540 amyloid-beta binding	IDA PMID:8089103 Isoform-specific binding of apolipoprotein E to beta-amyloid...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0005576 extracellular region	IDA PMID:8089103 Isoform-specific binding of apolipoprotein E to beta-amyloid...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0010877 lipid transport involved in lipid storage	ISS GO_REF:0000024	ACCEPT	Summary: lipid transport involved in lipid storage is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0070328 triglyceride homeostasis	ISS GO_REF:0000024	ACCEPT	Summary: triglyceride homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0005783 endoplasmic reticulum	IDA PMID:25122793 Apolipoprotein E likely contributes to a maturation step of ...	KEEP AS NON CORE	Summary: endoplasmic reticulum is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005794 Golgi apparatus	IDA PMID:25122793 Apolipoprotein E likely contributes to a maturation step of ...	KEEP AS NON CORE	Summary: Golgi apparatus is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0090090 negative regulation of canonical Wnt signaling pathway	TAS PMID:22988876 The importance of Wnt signalling for neurodegeneration in Pa...	KEEP AS NON CORE	Summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:1903561 extracellular vesicle	HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi...	KEEP AS NON CORE	Summary: APOE localization to extracellular vesicle is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0019068 virion assembly	IMP PMID:25122793 Apolipoprotein E likely contributes to a maturation step of ...	KEEP AS NON CORE	Summary: virion assembly is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0044794 host-mediated activation of viral process	IMP PMID:25122793 Apolipoprotein E likely contributes to a maturation step of ...	KEEP AS NON CORE	Summary: host-mediated activation of viral process is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: APOE localization to extracellular exosome is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	KEEP AS NON CORE	Summary: membrane is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005576 extracellular region	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:1903002 positive regulation of lipid transport across blood-brain barrier	IDA PMID:24345162 Reduction in DHA transport to the brain of mice expressing h...	ACCEPT	Summary: positive regulation of lipid transport across blood-brain barrier is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0046889 positive regulation of lipid biosynthetic process	IDA PMID:12042316 Apolipoprotein E (ApoE) isoform-dependent lipid release from...	ACCEPT	Summary: positive regulation of lipid biosynthetic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:1902995 positive regulation of phospholipid efflux	IDA PMID:12042316 Apolipoprotein E (ApoE) isoform-dependent lipid release from...	ACCEPT	Summary: positive regulation of phospholipid efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0010875 positive regulation of cholesterol efflux	IDA PMID:12042316 Apolipoprotein E (ApoE) isoform-dependent lipid release from...	ACCEPT	Summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0017038 protein import	IDA PMID:24446231 Apolipoproteins E and J interfere with amyloid-beta uptake b...	KEEP AS NON CORE	Summary: protein import is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:1900221 regulation of amyloid-beta clearance	IDA PMID:24446231 Apolipoproteins E and J interfere with amyloid-beta uptake b...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid-beta clearance, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0015909 long-chain fatty acid transport	IDA PMID:24345162 Reduction in DHA transport to the brain of mice expressing h...	ACCEPT	Summary: long-chain fatty acid transport is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0055089 fatty acid homeostasis	IDA PMID:24345162 Reduction in DHA transport to the brain of mice expressing h...	ACCEPT	Summary: fatty acid homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:1902430 negative regulation of amyloid-beta formation	IDA PMID:24154541 Human APOE genotype affects intraneuronal Aβ1-42 accumulatio...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid-beta formation, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	KEEP AS NON CORE	Summary: nucleus is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005515 protein binding	IPI PMID:8245722 Identification of disulfide-linked apolipoprotein species in...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0042803 protein homodimerization activity	IPI PMID:8245722 Identification of disulfide-linked apolipoprotein species in...	KEEP AS NON CORE	Summary: protein homodimerization activity reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0072562 blood microparticle	HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d...	ACCEPT	Summary: APOE is appropriately localized to blood microparticle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: APOE localization to extracellular exosome is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: APOE localization to extracellular exosome is supported, especially in extracellular vesicle and multivesicular-body contexts. Reason: This location is real and biologically useful, but it is secondary to APOE's core secreted lipoprotein-particle role. Supporting Evidence: PMID:26387950 Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes.
GO:0005576 extracellular region	TAS Reactome:R-HSA-174657	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-174660	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-174690	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-174739	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-174757	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2395768	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2395784	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2404131	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2423785	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2507854	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-266303	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-8869590	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-9031512	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005576 extracellular region	TAS Reactome:R-HSA-9612243	ACCEPT	Summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0005769 early endosome	TAS Reactome:R-HSA-2404131	KEEP AS NON CORE	Summary: early endosome is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005769 early endosome	TAS Reactome:R-HSA-2404140	KEEP AS NON CORE	Summary: early endosome is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005769 early endosome	TAS Reactome:R-HSA-2429643	KEEP AS NON CORE	Summary: early endosome is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-174657	KEEP AS NON CORE	Summary: plasma membrane is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-174706	KEEP AS NON CORE	Summary: plasma membrane is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0030669 clathrin-coated endocytic vesicle membrane	TAS Reactome:R-HSA-174706	KEEP AS NON CORE	Summary: clathrin-coated endocytic vesicle membrane is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2507854	KEEP AS NON CORE	Summary: endocytic vesicle lumen is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0032489 regulation of Cdc42 protein signal transduction	IDA PMID:16443932 Apolipoprotein A-I activates Cdc42 signaling through the ABC...	KEEP AS NON CORE	Summary: regulation of Cdc42 protein signal transduction is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0034361 very-low-density lipoprotein particle	IDA PMID:17154273 Proteomic analysis of human very low-density lipoprotein by ...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034372 very-low-density lipoprotein particle remodeling	IDA PMID:15654758 Apolipoprotein E is the major physiological activator of lec...	ACCEPT	Summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0060228 phosphatidylcholine-sterol O-acyltransferase activator activity	IDA PMID:15654758 Apolipoprotein E is the major physiological activator of lec...	ACCEPT	Summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific activity within its lipoprotein remodeling role. Reason: LCAT activation is a mechanistically specific APOE molecular function tied to cholesterol esterification and lipoprotein remodeling. Supporting Evidence: PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0045541 negative regulation of cholesterol biosynthetic process	IDA PMID:1917954 Mechanisms of inhibition by apolipoprotein C of apolipoprote...	ACCEPT	Summary: negative regulation of cholesterol biosynthetic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0005319 lipid carrier activity	IDA PMID:17305370 The C-terminal lipid-binding domain of apolipoprotein E is a...	ACCEPT	Summary: APOE lipid carrier activity is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0034380 high-density lipoprotein particle assembly	IDA PMID:17305370 The C-terminal lipid-binding domain of apolipoprotein E is a...	ACCEPT	Summary: high-density lipoprotein particle assembly is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid binding, ABCA1-dependent efflux, and LCAT activation. Supporting Evidence: PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:14754908 ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo. PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0034384 high-density lipoprotein particle clearance	IDA PMID:210175 Apoprotein (E--A-II) complex of human plasma lipoproteins. I...	ACCEPT	Summary: high-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid binding, ABCA1-dependent efflux, and LCAT activation. Supporting Evidence: PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:14754908 ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo. PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0010875 positive regulation of cholesterol efflux	IGI PMID:12401887 Evidence for differential effects of apoE3 and apoE4 on HDL ...	ACCEPT	Summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0010875 positive regulation of cholesterol efflux	IDA PMID:14754908 Molecular interactions between apoE and ABCA1: impact on apo...	ACCEPT	Summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0034372 very-low-density lipoprotein particle remodeling	IGI PMID:12401887 Evidence for differential effects of apoE3 and apoE4 on HDL ...	ACCEPT	Summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0034375 high-density lipoprotein particle remodeling	IGI PMID:12401887 Evidence for differential effects of apoE3 and apoE4 on HDL ...	ACCEPT	Summary: high-density lipoprotein particle remodeling is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid binding, ABCA1-dependent efflux, and LCAT activation. Supporting Evidence: PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:14754908 ABCA1 is essential for the biogenesis of high density-sized lipoprotein containing only apoE particles in vivo. PMID:15654758 We conclude that apoE is a more significant activator of LCAT than apoA-I on mouse apoB lipoproteins.
GO:0070326 very-low-density lipoprotein particle receptor binding	IPI PMID:12950167 Domains of apoE required for binding to apoE receptor 2 and ...	ACCEPT	Summary: APOE very-low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0070326 very-low-density lipoprotein particle receptor binding	IDA PMID:1384047 Rabbit very low density lipoprotein receptor: a low density ...	ACCEPT	Summary: APOE very-low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0006898 receptor-mediated endocytosis	IDA PMID:1917954 Mechanisms of inhibition by apolipoprotein C of apolipoprote...	ACCEPT	Summary: receptor-mediated endocytosis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing lipoproteins and remnants. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034447 very-low-density lipoprotein particle clearance	IDA PMID:1917954 Mechanisms of inhibition by apolipoprotein C of apolipoprote...	ACCEPT	Summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0034447 very-low-density lipoprotein particle clearance	IMP PMID:9649566 Type III hyperlipoproteinemia and spontaneous atherosclerosi...	ACCEPT	Summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0032805 positive regulation of low-density lipoprotein particle receptor catabolic process	IDA PMID:15950758 Regulation of ApoE receptor proteolysis by ligand binding.	ACCEPT	Summary: positive regulation of low-density lipoprotein particle receptor catabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing lipoproteins and remnants. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0042802 identical protein binding	IDA PMID:4066713 Behavior of human apolipoprotein E in aqueous solutions and ...	KEEP AS NON CORE	Summary: identical protein binding reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0034361 very-low-density lipoprotein particle	IDA PMID:8245722 Identification of disulfide-linked apolipoprotein species in...	ACCEPT	Summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034362 low-density lipoprotein particle	IDA PMID:8245722 Identification of disulfide-linked apolipoprotein species in...	ACCEPT	Summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034363 intermediate-density lipoprotein particle	IDA PMID:17336988 Fractionation of cholesteryl ester rich intermediate density...	ACCEPT	Summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034364 high-density lipoprotein particle	IDA PMID:210174 Apoprotein (E--A-II) complex of human plasma lipoproteins. I...	ACCEPT	Summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0034382 chylomicron remnant clearance	IMP PMID:7175379 Studies of familial type III hyperlipoproteinemia using as a...	ACCEPT	Summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: APOE-dependent receptor and proteoglycan interactions support remnant and triglyceride-rich lipoprotein clearance. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0033344 cholesterol efflux	IDA PMID:11162594 Apolipoprotein specificity for lipid efflux by the human ABC...	ACCEPT	Summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0033700 phospholipid efflux	IDA PMID:11162594 Apolipoprotein specificity for lipid efflux by the human ABC...	ACCEPT	Summary: phospholipid efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0010544 negative regulation of platelet activation	IDA PMID:8995232 Apolipoprotein E inhibits platelet aggregation through the L...	KEEP AS NON CORE	Summary: APOE-associated negative regulation of platelet activation is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8995232 We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway.
GO:0005737 cytoplasm	NAS PMID:8083695 Apolipoprotein E is localized to the cytoplasm of human cort...	KEEP AS NON CORE	Summary: cytoplasm is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0030425 dendrite	NAS PMID:8083695 Apolipoprotein E is localized to the cytoplasm of human cort...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including dendrite, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0043025 neuronal cell body	NAS PMID:8083695 Apolipoprotein E is localized to the cytoplasm of human cort...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including neuronal cell body, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0048156 tau protein binding	IPI PMID:7566652 ApoE3 binding to tau tandem repeat I is abolished by tau ser...	KEEP AS NON CORE	Summary: tau protein binding reflects APOE oligomerization, structural participation, or disease-relevant binding rather than its primary lipid-transfer activity. Reason: Retain as non-core because APOE self-association and disease-relevant partner binding are real but less informative than specific lipid, receptor, and lipoprotein annotations. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0001937 negative regulation of endothelial cell proliferation	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: APOE-associated negative regulation of endothelial cell proliferation is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:9685360 Taken together, these results suggest that apoE has cytostatic functions in the vessel wall
GO:0016209 antioxidant activity	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: APOE-associated antioxidant activity is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance.
GO:0030195 negative regulation of blood coagulation	IDA PMID:8995232 Apolipoprotein E inhibits platelet aggregation through the L...	KEEP AS NON CORE	Summary: APOE-associated negative regulation of blood coagulation is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8995232 We conclude that apoE inhibits platelet aggregation through the L-arginine:NO signal transduction pathway.
GO:0043537 negative regulation of blood vessel endothelial cell migration	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: APOE-associated negative regulation of blood vessel endothelial cell migration is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:9685360 Taken together, these results suggest that apoE has cytostatic functions in the vessel wall
GO:0043691 reverse cholesterol transport	IDA PMID:8127890 A plasma lipoprotein containing only apolipoprotein E and wi...	ACCEPT	Summary: reverse cholesterol transport is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0046911 metal chelating activity	IDA PMID:9685360 Apolipoprotein E inhibits platelet-derived growth factor-ind...	KEEP AS NON CORE	Summary: APOE-associated metal chelating activity is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance.
GO:0005543 phospholipid binding	IDA PMID:4066713 Behavior of human apolipoprotein E in aqueous solutions and ...	ACCEPT	Summary: APOE phospholipid binding is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0006641 triglyceride metabolic process	IMP PMID:3771793 Familial apolipoprotein E deficiency.	ACCEPT	Summary: triglyceride metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0006641 triglyceride metabolic process	IDA PMID:9649566 Type III hyperlipoproteinemia and spontaneous atherosclerosi...	ACCEPT	Summary: triglyceride metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0008201 heparin binding	IDA PMID:2745454 Apolipoprotein E mediates binding of normal very low density...	ACCEPT	Summary: APOE heparin binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0008203 cholesterol metabolic process	IMP PMID:3771793 Familial apolipoprotein E deficiency.	ACCEPT	Summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0008203 cholesterol metabolic process	IDA PMID:9649566 Type III hyperlipoproteinemia and spontaneous atherosclerosi...	ACCEPT	Summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0042627 chylomicron	IDA PMID:16935699 Apolipoprotein E enrichment of immuno-separated chylomicron ...	ACCEPT	Summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0042632 cholesterol homeostasis	IDA PMID:9649566 Type III hyperlipoproteinemia and spontaneous atherosclerosi...	ACCEPT	Summary: cholesterol homeostasis is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: This process falls within APOE's core role in lipid transport, lipoprotein particle metabolism, and lipid homeostasis. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE
GO:0050750 low-density lipoprotein particle receptor binding	IDA PMID:210175 Apoprotein (E--A-II) complex of human plasma lipoproteins. I...	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0051044 positive regulation of membrane protein ectodomain proteolysis	IDA PMID:15950758 Regulation of ApoE receptor proteolysis by ligand binding.	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for positive regulation of membrane protein ectodomain proteolysis, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0050750 low-density lipoprotein particle receptor binding	IPI PMID:17326667 Apolipoprotein A-V interaction with members of the low densi...	ACCEPT	Summary: APOE low-density lipoprotein particle receptor binding supports receptor- or proteoglycan-dependent uptake of APOE-containing lipoprotein particles. Reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and particle uptake. Supporting Evidence: PMID:2762297 We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis of cholesteryl esters contained in lipoproteins that are enriched in apo E. PMID:7635945 ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3. PMID:23676495 We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV.
GO:0042627 chylomicron	IDA PMID:8245722 Identification of disulfide-linked apolipoprotein species in...	ACCEPT	Summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated with plasma and tissue lipoprotein particles. Reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of action in lipid transport and lipoprotein clearance. Supporting Evidence: PMID:8340399 These results indicate lipoprotein association modulates the clearance of apoE PMID:9488694 Exogenously applied lipid-free apoE readily bound to the ECM; however, increasing the lipid content decreased its association.
GO:0007186 G protein-coupled receptor signaling pathway	IDA PMID:16443932 Apolipoprotein A-I activates Cdc42 signaling through the ABC...	KEEP AS NON CORE	Summary: G protein-coupled receptor signaling pathway is plausible APOE-associated signaling or regulatory biology, but it is not the core apolipoprotein function. Reason: Retain as non-core because APOE can signal through receptors and alter downstream pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor interactions.
GO:0033344 cholesterol efflux	IDA PMID:16443932 Apolipoprotein A-I activates Cdc42 signaling through the ABC...	ACCEPT	Summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or clearance biology. Reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and CNS-relevant cell systems. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ.
GO:0005515 protein binding	IPI PMID:7972031 Isoform-specific interactions of apolipoprotein E with micro...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation for APOE. Reason: The underlying interaction may be real, but this term is too generic for APOE; specific receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or lipid-transfer terms are more informative.
GO:0008289 lipid binding	IDA PMID:4066713 Behavior of human apolipoprotein E in aqueous solutions and ...	ACCEPT	Summary: APOE lipid binding is part of its core exchangeable apolipoprotein role in lipid and sterol transport. Reason: APOE lipid/phospholipid binding and cholesterol transfer underlie cholesterol/phospholipid efflux and HDL-like particle assembly. Supporting Evidence: PMID:11162594 ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control cells. PMID:17305370 the CT lipid-binding domain of apoE encompassing amino acids 222-299 is necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly. PMID:4066713 The results are consistent with a model that amphiphilic alpha-helical conformation is responsible both for self-association and surface binding
GO:0001540 amyloid-beta binding	IDA PMID:11305869 Quantitation of apoE domains in Alzheimer disease brain sugg...	KEEP AS NON CORE	Summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is secondary to its core apolipoprotein lipid-transport role. Reason: Amyloid-related annotations should be retained as disease-relevant non-core biology rather than treated as APOE's primary evolved molecular function. Supporting Evidence: PMID:25207746 apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth.
GO:0005737 cytoplasm	TAS PMID:9622609 The neurobiology of apolipoproteins and their receptors in t...	KEEP AS NON CORE	Summary: cytoplasm is retained as APOE-associated contextual biology, not as the core apolipoprotein activity. Reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is plausible enough to retain outside the core function set.
GO:0007271 synaptic transmission, cholinergic	TAS PMID:9622609 The neurobiology of apolipoproteins and their receptors in t...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including synaptic transmission, cholinergic, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0030516 regulation of axon extension	TAS PMID:9622609 The neurobiology of apolipoproteins and their receptors in t...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including regulation of axon extension, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
GO:0000302 response to reactive oxygen species	NAS PMID:11743999 Apolipoprotein E modulates Alzheimer's Abeta(1-42)-induced o...	KEEP AS NON CORE	Summary: APOE-associated response to reactive oxygen species is secondary vascular, antioxidant, or stress-response biology. Reason: This annotation has plausible experimental support but should not be promoted above APOE's primary role in lipid transport and lipoprotein clearance.
GO:0007010 cytoskeleton organization	TAS PMID:9622609 The neurobiology of apolipoproteins and their receptors in t...	KEEP AS NON CORE	Summary: cytoskeleton organization is retained as non-core APOE-associated biology pending a deeper reference-specific adjudication. Reason: The annotation is not part of the primary lipid-transport and lipoprotein-clearance function set, but available local evidence was not sufficient to remove it.
GO:0048168 regulation of neuronal synaptic plasticity	TAS PMID:9622609 The neurobiology of apolipoproteins and their receptors in t...	KEEP AS NON CORE	Summary: APOE influences neuronal or synaptic phenotypes including regulation of neuronal synaptic plasticity, largely through CNS lipid transport and receptor-dependent contexts. Reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity. Supporting Evidence: PMID:12042316 Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. PMID:24345162 Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.

📄 View Raw YAML

id: P02649
gene_symbol: APOE
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'Apolipoprotein E is a secreted exchangeable apolipoprotein that associates with plasma,
  interstitial, and central-nervous-system lipoprotein particles. Through amphipathic lipid-binding domains
  and receptor-binding activity, APOE mediates cholesterol and phospholipid efflux, high-density lipoprotein
  particle formation/remodeling, and receptor- or proteoglycan-dependent clearance of chylomicron remnants,
  VLDL, IDL, LDL, and HDL particles. APOE is produced prominently by liver and by astrocytes and other
  glial cells in brain, where it supports lipid redistribution among cells. APOE also binds amyloid-beta,
  tau, immune receptors, extracellular matrix proteoglycans, and other partners, but these disease- or
  context-linked activities are secondary to its core lipid-transport and lipoprotein-clearance roles.'
existing_annotations:
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: APOE cholesterol transfer activity is part of its core exchangeable apolipoprotein role
      in lipid and sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0042627
    label: chylomicron
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated 
      with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: APOE phospholipid binding is part of its core exchangeable apolipoprotein role in lipid
      and sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0033344
    label: cholesterol efflux
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0033700
    label: phospholipid efflux
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: phospholipid efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0055090
    label: acylglycerol homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: acylglycerol homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0060228
    label: phosphatidylcholine-sterol O-acyltransferase activator activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific
      activity within its lipoprotein remodeling role.
    action: ACCEPT
    reason: LCAT activation is a mechanistically specific APOE molecular function tied to 
      cholesterol esterification and lipoprotein remodeling.
    supported_by:
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: APOE localization to extracellular vesicle is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005771
    label: multivesicular body
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: APOE localization to multivesicular body is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0006869
    label: lipid transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: lipid transport is part of APOE's core lipoprotein transport, remodeling, or clearance 
      biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: APOE lipid binding is part of its core exchangeable apolipoprotein role in lipid and 
      sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0042157
    label: lipoprotein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: lipoprotein metabolic process is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0098869
    label: cellular oxidant detoxification
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: APOE-associated cellular oxidant detoxification is secondary vascular, antioxidant, or 
      stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: APOE localization to extracellular vesicle is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:12950167
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15182176
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15615705
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17116874
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19758344
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20030366
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21163940
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21593558
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22528093
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24447298
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25122793
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26468283
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26921451
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28887769
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29507344
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30341064
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31270237
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7566652
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: negative regulation of gene expression is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0010875
    label: positive regulation of cholesterol efflux
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0010877
    label: lipid transport involved in lipid storage
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: lipid transport involved in lipid storage is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron
      projection development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0032438
    label: melanosome organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: melanosome organization is retained as APOE-associated contextual biology, not as the 
      core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034372
    label: very-low-density lipoprotein particle remodeling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0034374
    label: low-density lipoprotein particle remodeling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: low-density lipoprotein particle remodeling is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of apoptotic process is plausible APOE-associated signaling or regulatory 
      biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0043395
    label: heparan sulfate proteoglycan binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent 
      uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of innate immune response is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: negative regulation of inflammatory response is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0050807
    label: regulation of synapse organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including regulation of synapse 
      organization, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0060228
    label: phosphatidylcholine-sterol O-acyltransferase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific
      activity within its lipoprotein remodeling role.
    action: ACCEPT
    reason: LCAT activation is a mechanistically specific APOE molecular function tied to 
      cholesterol esterification and lipoprotein remodeling.
    supported_by:
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0070328
    label: triglyceride homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: triglyceride homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0071813
    label: lipoprotein particle binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: APOE lipoprotein particle binding supports receptor- or proteoglycan-dependent uptake 
      of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0071830
    label: triglyceride-rich lipoprotein particle clearance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: triglyceride-rich lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0090205
    label: positive regulation of cholesterol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol metabolic process is part of APOE's core lipoprotein
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0097006
    label: regulation of plasma lipoprotein particle levels
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: regulation of plasma lipoprotein particle levels is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, 
      largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0120020
    label: cholesterol transfer activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: APOE cholesterol transfer activity is part of its core exchangeable apolipoprotein role
      in lipid and sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:1900223
    label: positive regulation of amyloid-beta clearance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid-beta 
      clearance, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid fibril
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0001523
    label: retinoid metabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-975634
  qualifier: involved_in
  review:
    summary: retinoid metabolic process is retained as APOE-associated contextual biology, not as 
      the core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:2498325
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:30333625
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: EXP
  original_reference_id: PMID:26387950
  qualifier: located_in
  review:
    summary: APOE localization to extracellular vesicle is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2423785
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27559042
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0010642
    label: negative regulation of platelet-derived growth factor receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: involved_in
  review:
    summary: negative regulation of platelet-derived growth factor receptor signaling pathway is 
      plausible APOE-associated signaling or regulatory biology, but it is not the core 
      apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:9685360
      supporting_text: Taken together, these results suggest that apoE has cytostatic functions in 
        the vessel wall
- term:
    id: GO:0043409
    label: negative regulation of MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: involved_in
  review:
    summary: negative regulation of MAPK cascade is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:9685360
      supporting_text: Taken together, these results suggest that apoE has cytostatic functions in 
        the vessel wall
- term:
    id: GO:0034360
    label: chylomicron remnant
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to chylomicron remnant as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IDA
  original_reference_id: PMID:8995232
  qualifier: involved_in
  review:
    summary: negative regulation of inflammatory response is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0140077
    label: positive regulation of lipoprotein transport
  evidence_type: IDA
  original_reference_id: PMID:8300609
  qualifier: involved_in
  review:
    summary: positive regulation of lipoprotein transport is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0048018
    label: receptor ligand activity
  evidence_type: IDA
  original_reference_id: PMID:27477018
  qualifier: enables
  review:
    summary: receptor ligand activity is plausible APOE-associated signaling or regulatory biology, 
      but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:27477018
      supporting_text: we identified a set of lipoprotein particles (including LDL) and 
        apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2.
- term:
    id: GO:0071402
    label: cellular response to lipoprotein particle stimulus
  evidence_type: IDA
  original_reference_id: PMID:27477018
  qualifier: involved_in
  review:
    summary: cellular response to lipoprotein particle stimulus is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0043083
    label: synaptic cleft
  evidence_type: IEP
  original_reference_id: PMID:22637583
  qualifier: is_active_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including synaptic cleft, largely 
      through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0043083
    label: synaptic cleft
  evidence_type: IDA
  original_reference_id: PMID:22637583
  qualifier: is_active_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including synaptic cleft, largely 
      through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEP
  original_reference_id: PMID:22637583
  qualifier: is_active_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, 
      largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IDA
  original_reference_id: PMID:22637583
  qualifier: is_active_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including glutamatergic synapse, 
      largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0038060
    label: nitric oxide-cGMP-mediated signaling
  evidence_type: IDA
  original_reference_id: PMID:8995232
  qualifier: involved_in
  review:
    summary: nitric oxide-cGMP-mediated signaling is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:8995232
      supporting_text: We conclude that apoE inhibits platelet aggregation through the L-arginine:NO
        signal transduction pathway.
- term:
    id: GO:0045429
    label: positive regulation of nitric oxide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:8995232
  qualifier: involved_in
  review:
    summary: positive regulation of nitric oxide biosynthetic process is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:8995232
      supporting_text: We conclude that apoE inhibits platelet aggregation through the L-arginine:NO
        signal transduction pathway.
- term:
    id: GO:0034382
    label: chylomicron remnant clearance
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: involved_in
  review:
    summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034447
    label: very-low-density lipoprotein particle clearance
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0043395
    label: heparan sulfate proteoglycan binding
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: enables
  review:
    summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent 
      uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0045807
    label: positive regulation of endocytosis
  evidence_type: IDA
  original_reference_id: PMID:7683668
  qualifier: involved_in
  review:
    summary: positive regulation of endocytosis is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing 
      lipoproteins and remnants.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:8089103
  qualifier: enables
  review:
    summary: protein homodimerization activity reflects APOE oligomerization, structural 
      participation, or disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:9211985
  qualifier: enables
  review:
    summary: protein homodimerization activity reflects APOE oligomerization, structural 
      participation, or disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0097487
    label: multivesicular body, internal vesicle
  evidence_type: IDA
  original_reference_id: PMID:26387950
  qualifier: located_in
  review:
    summary: APOE localization to multivesicular body, internal vesicle is supported, especially in 
      extracellular vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26387950
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0032438
    label: melanosome organization
  evidence_type: IMP
  original_reference_id: PMID:26387950
  qualifier: involved_in
  review:
    summary: melanosome organization is retained as APOE-associated contextual biology, not as the 
      core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0042470
    label: melanosome
  evidence_type: IDA
  original_reference_id: PMID:26387950
  qualifier: located_in
  review:
    summary: melanosome is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: IDA
  original_reference_id: PMID:26387950
  qualifier: located_in
  review:
    summary: APOE localization to extracellular exosome is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IPI
  original_reference_id: PMID:15654758
  qualifier: enables
  review:
    summary: Generic enzyme binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0090205
    label: positive regulation of cholesterol metabolic process
  evidence_type: IDA
  original_reference_id: PMID:15654758
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol metabolic process is part of APOE's core lipoprotein
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0097113
    label: AMPA glutamate receptor clustering
  evidence_type: IDA
  original_reference_id: PMID:24328732
  qualifier: acts_upstream_of_or_within_positive_effect
  review:
    summary: APOE influences neuronal or synaptic phenotypes including AMPA glutamate receptor 
      clustering, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0097114
    label: NMDA glutamate receptor clustering
  evidence_type: IDA
  original_reference_id: PMID:24328732
  qualifier: acts_upstream_of_or_within_positive_effect
  review:
    summary: APOE influences neuronal or synaptic phenotypes including NMDA glutamate receptor 
      clustering, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:16805831
  qualifier: involved_in
  review:
    summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0048662
    label: negative regulation of smooth muscle cell proliferation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: acts_upstream_of
  review:
    summary: negative regulation of smooth muscle cell proliferation is retained as non-core 
      APOE-associated biology pending a deeper reference-specific adjudication.
    action: KEEP_AS_NON_CORE
    reason: The annotation is not part of the primary lipid-transport and lipoprotein-clearance 
      function set, but available local evidence was not sufficient to remove it.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-976734
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0046983
    label: protein dimerization activity
  evidence_type: IPI
  original_reference_id: PMID:22138302
  qualifier: enables
  review:
    summary: protein dimerization activity reflects APOE oligomerization, structural participation, 
      or disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0060999
    label: positive regulation of dendritic spine development
  evidence_type: IDA
  original_reference_id: PMID:24328732
  qualifier: acts_upstream_of_or_within
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of 
      dendritic spine development, largely through CNS lipid transport and receptor-dependent 
      contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:1902952
    label: positive regulation of dendritic spine maintenance
  evidence_type: IDA
  original_reference_id: PMID:24328732
  qualifier: acts_upstream_of_or_within
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of 
      dendritic spine maintenance, largely through CNS lipid transport and receptor-dependent 
      contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0005102
    label: signaling receptor binding
  evidence_type: IPI
  original_reference_id: PMID:27477018
  qualifier: enables
  review:
    summary: signaling receptor binding is plausible APOE-associated signaling or regulatory 
      biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:27477018
      supporting_text: we identified a set of lipoprotein particles (including LDL) and 
        apolipoproteins (including CLU/APOJ and APOE) as ligands of TREM2.
- term:
    id: GO:0043254
    label: regulation of protein-containing complex assembly
  evidence_type: IDA
  original_reference_id: PMID:25207746
  qualifier: involved_in
  review:
    summary: regulation of protein-containing complex assembly is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:25207746
  qualifier: enables
  review:
    summary: Generic protein-containing complex binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30448281
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:1902991
    label: regulation of amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:28164773
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid precursor 
      protein catabolic process, but this is secondary to its core apolipoprotein lipid-transport 
      role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:1900223
    label: positive regulation of amyloid-beta clearance
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid-beta 
      clearance, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:1905907
    label: negative regulation of amyloid fibril formation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid fibril
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0010596
    label: negative regulation of endothelial cell migration
  evidence_type: IMP
  original_reference_id: PMID:23142051
  qualifier: involved_in
  review:
    summary: APOE-associated negative regulation of endothelial cell migration is secondary 
      vascular, antioxidant, or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:9685360
      supporting_text: Taken together, these results suggest that apoE has cytostatic functions in 
        the vessel wall
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:27044754
  qualifier: involved_in
  review:
    summary: negative regulation of protein secretion is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0031175
    label: neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:8939961
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including neuron projection 
      development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0033344
    label: cholesterol efflux
  evidence_type: IDA
  original_reference_id: PMID:23620513
  qualifier: involved_in
  review:
    summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0042158
    label: lipoprotein biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:23620513
  qualifier: involved_in
  review:
    summary: lipoprotein biosynthetic process is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid
      binding, ABCA1-dependent efflux, and LCAT activation.
    supported_by:
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:14754908
      supporting_text: ABCA1 is essential for the biogenesis of high density-sized lipoprotein 
        containing only apoE particles in vivo.
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0043395
    label: heparan sulfate proteoglycan binding
  evidence_type: IDA
  original_reference_id: PMID:23676495
  qualifier: enables
  review:
    summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent 
      uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0071830
    label: triglyceride-rich lipoprotein particle clearance
  evidence_type: IMP
  original_reference_id: PMID:23676495
  qualifier: involved_in
  review:
    summary: triglyceride-rich lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034382
    label: chylomicron remnant clearance
  evidence_type: IDA
  original_reference_id: PMID:1911868
  qualifier: involved_in
  review:
    summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:8340399
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IDA
  original_reference_id: PMID:9488694
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular matrix as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:8340399
  qualifier: enables
  review:
    summary: identical protein binding reflects APOE oligomerization, structural participation, or 
      disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0043395
    label: heparan sulfate proteoglycan binding
  evidence_type: IDA
  original_reference_id: PMID:9488694
  qualifier: enables
  review:
    summary: APOE heparan sulfate proteoglycan binding supports receptor- or proteoglycan-dependent 
      uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0071831
    label: intermediate-density lipoprotein particle clearance
  evidence_type: IDA
  original_reference_id: PMID:1917954
  qualifier: involved_in
  review:
    summary: intermediate-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034447
    label: very-low-density lipoprotein particle clearance
  evidence_type: IDA
  original_reference_id: PMID:2762297
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:2280190
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:8071364
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:2280190
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:2280190
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a 
      secreted apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:2280190
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:8071364
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14754908
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:7635945
  qualifier: enables
  review:
    summary: APOE heparin binding supports receptor- or proteoglycan-dependent uptake of 
      APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:14754908
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034380
    label: high-density lipoprotein particle assembly
  evidence_type: IDA
  original_reference_id: PMID:14754908
  qualifier: involved_in
  review:
    summary: high-density lipoprotein particle assembly is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid
      binding, ABCA1-dependent efflux, and LCAT activation.
    supported_by:
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:14754908
      supporting_text: ABCA1 is essential for the biogenesis of high density-sized lipoprotein 
        containing only apoE particles in vivo.
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: IDA
  original_reference_id: PMID:7635945
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: IDA
  original_reference_id: PMID:1530612
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:28111074
  qualifier: involved_in
  review:
    summary: positive regulation of DNA-templated transcription is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:28111074
      supporting_text: ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a 
        MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
- term:
    id: GO:0061136
    label: regulation of proteasomal protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:28111074
  qualifier: involved_in
  review:
    summary: regulation of proteasomal protein catabolic process is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:28111074
      supporting_text: ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a 
        MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IMP
  original_reference_id: PMID:28111074
  qualifier: involved_in
  review:
    summary: positive regulation of ERK1 and ERK2 cascade is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
    supported_by:
    - reference_id: PMID:28111074
      supporting_text: ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a 
        MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27068509
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:20551380
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: negative regulation of gene expression is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0007616
    label: long-term memory
  evidence_type: IGI
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including long-term memory, largely 
      through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0035641
    label: locomotory exploration behavior
  evidence_type: IMP
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including locomotory exploration 
      behavior, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0042632
    label: cholesterol homeostasis
  evidence_type: IGI
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: cholesterol homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0051044
    label: positive regulation of membrane protein ectodomain proteolysis
  evidence_type: IGI
  original_reference_id: PMID:25015123
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of membrane 
      protein ectodomain proteolysis, but this is secondary to its core apolipoprotein 
      lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0051246
    label: regulation of protein metabolic process
  evidence_type: IGI
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: regulation of protein metabolic process is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0061771
    label: response to caloric restriction
  evidence_type: IGI
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: response to caloric restriction is retained as APOE-associated contextual biology, not 
      as the core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0090181
    label: regulation of cholesterol metabolic process
  evidence_type: IGI
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: regulation of cholesterol metabolic process is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:2000822
    label: regulation of behavioral fear response
  evidence_type: IMP
  original_reference_id: PMID:24412220
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including regulation of behavioral fear
      response, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0034365
    label: discoidal high-density lipoprotein particle
  evidence_type: TAS
  original_reference_id: PMID:22383525
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to discoidal high-density lipoprotein particle as a 
      secreted apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: NAS
  original_reference_id: PMID:20005821
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:1905908
    label: positive regulation of amyloid fibril formation
  evidence_type: TAS
  original_reference_id: PMID:20005821
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid fibril
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:25207746
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:1905906
    label: regulation of amyloid fibril formation
  evidence_type: IDA
  original_reference_id: PMID:25207746
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid fibril 
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IPI
  original_reference_id: PMID:22138302
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0005198
    label: structural molecule activity
  evidence_type: TAS
  original_reference_id: PMID:22138302
  qualifier: enables
  review:
    summary: structural molecule activity reflects APOE oligomerization, structural participation, 
      or disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: TAS
  original_reference_id: PMID:22138302
  qualifier: involved_in
  review:
    summary: receptor-mediated endocytosis is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing 
      lipoproteins and remnants.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a 
      secreted apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:1905908
    label: positive regulation of amyloid fibril formation
  evidence_type: TAS
  original_reference_id: PMID:9228033
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of amyloid fibril
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:1990777
    label: lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:22138302
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to lipoprotein particle as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IPI
  original_reference_id: PMID:9211985
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0042982
    label: amyloid precursor protein metabolic process
  evidence_type: IDA
  original_reference_id: PMID:21593558
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid precursor protein metabolic 
      process, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:7592957
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron
      projection development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0010977
    label: negative regulation of neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:7592957
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including negative regulation of neuron
      projection development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:1905890
    label: regulation of cellular response to very-low-density lipoprotein particle stimulus
  evidence_type: IDA
  original_reference_id: PMID:7592957
  qualifier: involved_in
  review:
    summary: regulation of cellular response to very-low-density lipoprotein particle stimulus is 
      part of APOE's core lipoprotein transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron
      projection development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0010976
    label: positive regulation of neuron projection development
  evidence_type: IDA
  original_reference_id: PMID:23845000
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including positive regulation of neuron
      projection development, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:1900272
    label: negative regulation of long-term synaptic potentiation
  evidence_type: IDA
  original_reference_id: PMID:16273551
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including negative regulation of 
      long-term synaptic potentiation, largely through CNS lipid transport and receptor-dependent 
      contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:16805831
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0051248
    label: negative regulation of protein metabolic process
  evidence_type: IGI
  original_reference_id: PMID:16805831
  qualifier: involved_in
  review:
    summary: negative regulation of protein metabolic process is plausible APOE-associated signaling
      or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:16805831
  qualifier: involved_in
  review:
    summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  qualifier: located_in
  review:
    summary: endoplasmic reticulum lumen is retained as APOE-associated contextual biology, not as 
      the core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:9211985
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:9211985
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:9211985
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a 
      secreted apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:9211985
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IPI
  original_reference_id: PMID:9003062
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0045807
    label: positive regulation of endocytosis
  evidence_type: IDA
  original_reference_id: PMID:8300609
  qualifier: involved_in
  review:
    summary: positive regulation of endocytosis is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing 
      lipoproteins and remnants.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:8089103
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:8089103
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0010877
    label: lipid transport involved in lipid storage
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: lipid transport involved in lipid storage is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0070328
    label: triglyceride homeostasis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: triglyceride homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:25122793
  qualifier: located_in
  review:
    summary: endoplasmic reticulum is retained as APOE-associated contextual biology, not as the 
      core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:25122793
  qualifier: located_in
  review:
    summary: Golgi apparatus is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:22988876
  qualifier: involved_in
  review:
    summary: negative regulation of canonical Wnt signaling pathway is plausible APOE-associated 
      signaling or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:1903561
    label: extracellular vesicle
  evidence_type: HDA
  original_reference_id: PMID:24769233
  qualifier: located_in
  review:
    summary: APOE localization to extracellular vesicle is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0019068
    label: virion assembly
  evidence_type: IMP
  original_reference_id: PMID:25122793
  qualifier: involved_in
  review:
    summary: virion assembly is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0044794
    label: host-mediated activation of viral process
  evidence_type: IMP
  original_reference_id: PMID:25122793
  qualifier: involved_in
  review:
    summary: host-mediated activation of viral process is retained as APOE-associated contextual 
      biology, not as the core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    summary: APOE localization to extracellular exosome is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: membrane is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:16502470
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:1903002
    label: positive regulation of lipid transport across blood-brain barrier
  evidence_type: IDA
  original_reference_id: PMID:24345162
  qualifier: involved_in
  review:
    summary: positive regulation of lipid transport across blood-brain barrier is part of APOE's 
      core lipoprotein transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0046889
    label: positive regulation of lipid biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:12042316
  qualifier: involved_in
  review:
    summary: positive regulation of lipid biosynthetic process is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:1902995
    label: positive regulation of phospholipid efflux
  evidence_type: IDA
  original_reference_id: PMID:12042316
  qualifier: involved_in
  review:
    summary: positive regulation of phospholipid efflux is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0010875
    label: positive regulation of cholesterol efflux
  evidence_type: IDA
  original_reference_id: PMID:12042316
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0017038
    label: protein import
  evidence_type: IDA
  original_reference_id: PMID:24446231
  qualifier: involved_in
  review:
    summary: protein import is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:1900221
    label: regulation of amyloid-beta clearance
  evidence_type: IDA
  original_reference_id: PMID:24446231
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for regulation of amyloid-beta clearance,
      but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0015909
    label: long-chain fatty acid transport
  evidence_type: IDA
  original_reference_id: PMID:24345162
  qualifier: involved_in
  review:
    summary: long-chain fatty acid transport is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0055089
    label: fatty acid homeostasis
  evidence_type: IDA
  original_reference_id: PMID:24345162
  qualifier: involved_in
  review:
    summary: fatty acid homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:24154541
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for negative regulation of amyloid-beta 
      formation, but this is secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    summary: nucleus is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:8245722
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:8245722
  qualifier: enables
  review:
    summary: protein homodimerization activity reflects APOE oligomerization, structural 
      participation, or disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0072562
    label: blood microparticle
  evidence_type: HDA
  original_reference_id: PMID:22516433
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to blood microparticle as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: APOE localization to extracellular exosome is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  qualifier: located_in
  review:
    summary: APOE localization to extracellular exosome is supported, especially in extracellular 
      vesicle and multivesicular-body contexts.
    action: KEEP_AS_NON_CORE
    reason: This location is real and biologically useful, but it is secondary to APOE's core 
      secreted lipoprotein-particle role.
    supported_by:
    - reference_id: PMID:26387950
      supporting_text: Here, we show that ApoE is associated with intraluminal vesicles (ILV) within
        endosomes and remain associated with ILVs when they are secreted as exosomes.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174657
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174660
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174690
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174739
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174757
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2395768
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2395784
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2404131
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2423785
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2507854
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-266303
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869590
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9031512
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9612243
  qualifier: located_in
  review:
    summary: APOE is appropriately localized to extracellular region as a secreted apolipoprotein 
      associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2404131
  qualifier: located_in
  review:
    summary: early endosome is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2404140
  qualifier: located_in
  review:
    summary: early endosome is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2429643
  qualifier: located_in
  review:
    summary: early endosome is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174657
  qualifier: located_in
  review:
    summary: plasma membrane is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174706
  qualifier: located_in
  review:
    summary: plasma membrane is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0030669
    label: clathrin-coated endocytic vesicle membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-174706
  qualifier: located_in
  review:
    summary: clathrin-coated endocytic vesicle membrane is retained as APOE-associated contextual 
      biology, not as the core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0071682
    label: endocytic vesicle lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2507854
  qualifier: located_in
  review:
    summary: endocytic vesicle lumen is retained as APOE-associated contextual biology, not as the 
      core apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0032489
    label: regulation of Cdc42 protein signal transduction
  evidence_type: IDA
  original_reference_id: PMID:16443932
  qualifier: involved_in
  review:
    summary: regulation of Cdc42 protein signal transduction is plausible APOE-associated signaling 
      or regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:17154273
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034372
    label: very-low-density lipoprotein particle remodeling
  evidence_type: IDA
  original_reference_id: PMID:15654758
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0060228
    label: phosphatidylcholine-sterol O-acyltransferase activator activity
  evidence_type: IDA
  original_reference_id: PMID:15654758
  qualifier: enables
  review:
    summary: APOE can activate lecithin-cholesterol acyltransferase on apoB lipoproteins, a specific
      activity within its lipoprotein remodeling role.
    action: ACCEPT
    reason: LCAT activation is a mechanistically specific APOE molecular function tied to 
      cholesterol esterification and lipoprotein remodeling.
    supported_by:
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0045541
    label: negative regulation of cholesterol biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1917954
  qualifier: involved_in
  review:
    summary: negative regulation of cholesterol biosynthetic process is part of APOE's core 
      lipoprotein transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0005319
    label: lipid carrier activity
  evidence_type: IDA
  original_reference_id: PMID:17305370
  qualifier: enables
  review:
    summary: APOE lipid carrier activity is part of its core exchangeable apolipoprotein role in 
      lipid and sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0034380
    label: high-density lipoprotein particle assembly
  evidence_type: IDA
  original_reference_id: PMID:17305370
  qualifier: involved_in
  review:
    summary: high-density lipoprotein particle assembly is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid
      binding, ABCA1-dependent efflux, and LCAT activation.
    supported_by:
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:14754908
      supporting_text: ABCA1 is essential for the biogenesis of high density-sized lipoprotein 
        containing only apoE particles in vivo.
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0034384
    label: high-density lipoprotein particle clearance
  evidence_type: IDA
  original_reference_id: PMID:210175
  qualifier: involved_in
  review:
    summary: high-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid
      binding, ABCA1-dependent efflux, and LCAT activation.
    supported_by:
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:14754908
      supporting_text: ABCA1 is essential for the biogenesis of high density-sized lipoprotein 
        containing only apoE particles in vivo.
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0010875
    label: positive regulation of cholesterol efflux
  evidence_type: IGI
  original_reference_id: PMID:12401887
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0010875
    label: positive regulation of cholesterol efflux
  evidence_type: IDA
  original_reference_id: PMID:14754908
  qualifier: involved_in
  review:
    summary: positive regulation of cholesterol efflux is part of APOE's core lipoprotein transport,
      remodeling, or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0034372
    label: very-low-density lipoprotein particle remodeling
  evidence_type: IGI
  original_reference_id: PMID:12401887
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle remodeling is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0034375
    label: high-density lipoprotein particle remodeling
  evidence_type: IGI
  original_reference_id: PMID:12401887
  qualifier: involved_in
  review:
    summary: high-density lipoprotein particle remodeling is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE contributes to HDL-like particle formation and lipoprotein remodeling through lipid
      binding, ABCA1-dependent efflux, and LCAT activation.
    supported_by:
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:14754908
      supporting_text: ABCA1 is essential for the biogenesis of high density-sized lipoprotein 
        containing only apoE particles in vivo.
    - reference_id: PMID:15654758
      supporting_text: We conclude that apoE is a more significant activator of LCAT than apoA-I on 
        mouse apoB lipoproteins.
- term:
    id: GO:0070326
    label: very-low-density lipoprotein particle receptor binding
  evidence_type: IPI
  original_reference_id: PMID:12950167
  qualifier: enables
  review:
    summary: APOE very-low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0070326
    label: very-low-density lipoprotein particle receptor binding
  evidence_type: IDA
  original_reference_id: PMID:1384047
  qualifier: enables
  review:
    summary: APOE very-low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IDA
  original_reference_id: PMID:1917954
  qualifier: involved_in
  review:
    summary: receptor-mediated endocytosis is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing 
      lipoproteins and remnants.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034447
    label: very-low-density lipoprotein particle clearance
  evidence_type: IDA
  original_reference_id: PMID:1917954
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0034447
    label: very-low-density lipoprotein particle clearance
  evidence_type: IMP
  original_reference_id: PMID:9649566
  qualifier: involved_in
  review:
    summary: very-low-density lipoprotein particle clearance is part of APOE's core lipoprotein 
      transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0032805
    label: positive regulation of low-density lipoprotein particle receptor catabolic process
  evidence_type: IDA
  original_reference_id: PMID:15950758
  qualifier: involved_in
  review:
    summary: positive regulation of low-density lipoprotein particle receptor catabolic process is 
      part of APOE's core lipoprotein transport, remodeling, or clearance biology.
    action: ACCEPT
    reason: Receptor-mediated uptake is an essential mechanism for clearance of APOE-containing 
      lipoproteins and remnants.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IDA
  original_reference_id: PMID:4066713
  qualifier: enables
  review:
    summary: identical protein binding reflects APOE oligomerization, structural participation, or 
      disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0034361
    label: very-low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:8245722
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to very-low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034362
    label: low-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:8245722
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to low-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034363
    label: intermediate-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:17336988
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to intermediate-density lipoprotein particle as a 
      secreted apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034364
    label: high-density lipoprotein particle
  evidence_type: IDA
  original_reference_id: PMID:210174
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to high-density lipoprotein particle as a secreted 
      apolipoprotein associated with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0034382
    label: chylomicron remnant clearance
  evidence_type: IMP
  original_reference_id: PMID:7175379
  qualifier: involved_in
  review:
    summary: chylomicron remnant clearance is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: APOE-dependent receptor and proteoglycan interactions support remnant and 
      triglyceride-rich lipoprotein clearance.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0033344
    label: cholesterol efflux
  evidence_type: IDA
  original_reference_id: PMID:11162594
  qualifier: involved_in
  review:
    summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0033700
    label: phospholipid efflux
  evidence_type: IDA
  original_reference_id: PMID:11162594
  qualifier: involved_in
  review:
    summary: phospholipid efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0010544
    label: negative regulation of platelet activation
  evidence_type: IDA
  original_reference_id: PMID:8995232
  qualifier: involved_in
  review:
    summary: APOE-associated negative regulation of platelet activation is secondary vascular, 
      antioxidant, or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8995232
      supporting_text: We conclude that apoE inhibits platelet aggregation through the L-arginine:NO
        signal transduction pathway.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: NAS
  original_reference_id: PMID:8083695
  qualifier: located_in
  review:
    summary: cytoplasm is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: NAS
  original_reference_id: PMID:8083695
  qualifier: located_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including dendrite, largely through CNS
      lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: NAS
  original_reference_id: PMID:8083695
  qualifier: located_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including neuronal cell body, largely 
      through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0048156
    label: tau protein binding
  evidence_type: IPI
  original_reference_id: PMID:7566652
  qualifier: enables
  review:
    summary: tau protein binding reflects APOE oligomerization, structural participation, or 
      disease-relevant binding rather than its primary lipid-transfer activity.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE self-association and disease-relevant partner binding 
      are real but less informative than specific lipid, receptor, and lipoprotein annotations.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: involved_in
  review:
    summary: APOE-associated negative regulation of endothelial cell proliferation is secondary 
      vascular, antioxidant, or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:9685360
      supporting_text: Taken together, these results suggest that apoE has cytostatic functions in 
        the vessel wall
- term:
    id: GO:0016209
    label: antioxidant activity
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: enables
  review:
    summary: APOE-associated antioxidant activity is secondary vascular, antioxidant, or 
      stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
- term:
    id: GO:0030195
    label: negative regulation of blood coagulation
  evidence_type: IDA
  original_reference_id: PMID:8995232
  qualifier: involved_in
  review:
    summary: APOE-associated negative regulation of blood coagulation is secondary vascular, 
      antioxidant, or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8995232
      supporting_text: We conclude that apoE inhibits platelet aggregation through the L-arginine:NO
        signal transduction pathway.
- term:
    id: GO:0043537
    label: negative regulation of blood vessel endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: involved_in
  review:
    summary: APOE-associated negative regulation of blood vessel endothelial cell migration is 
      secondary vascular, antioxidant, or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:9685360
      supporting_text: Taken together, these results suggest that apoE has cytostatic functions in 
        the vessel wall
- term:
    id: GO:0043691
    label: reverse cholesterol transport
  evidence_type: IDA
  original_reference_id: PMID:8127890
  qualifier: involved_in
  review:
    summary: reverse cholesterol transport is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0046911
    label: metal chelating activity
  evidence_type: IDA
  original_reference_id: PMID:9685360
  qualifier: enables
  review:
    summary: APOE-associated metal chelating activity is secondary vascular, antioxidant, or 
      stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
- term:
    id: GO:0005543
    label: phospholipid binding
  evidence_type: IDA
  original_reference_id: PMID:4066713
  qualifier: enables
  review:
    summary: APOE phospholipid binding is part of its core exchangeable apolipoprotein role in lipid
      and sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0006641
    label: triglyceride metabolic process
  evidence_type: IMP
  original_reference_id: PMID:3771793
  qualifier: involved_in
  review:
    summary: triglyceride metabolic process is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0006641
    label: triglyceride metabolic process
  evidence_type: IDA
  original_reference_id: PMID:9649566
  qualifier: involved_in
  review:
    summary: triglyceride metabolic process is part of APOE's core lipoprotein transport, 
      remodeling, or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0008201
    label: heparin binding
  evidence_type: IDA
  original_reference_id: PMID:2745454
  qualifier: enables
  review:
    summary: APOE heparin binding supports receptor- or proteoglycan-dependent uptake of 
      APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IMP
  original_reference_id: PMID:3771793
  qualifier: involved_in
  review:
    summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0008203
    label: cholesterol metabolic process
  evidence_type: IDA
  original_reference_id: PMID:9649566
  qualifier: involved_in
  review:
    summary: cholesterol metabolic process is part of APOE's core lipoprotein transport, remodeling,
      or clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0042627
    label: chylomicron
  evidence_type: IDA
  original_reference_id: PMID:16935699
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated 
      with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0042632
    label: cholesterol homeostasis
  evidence_type: IDA
  original_reference_id: PMID:9649566
  qualifier: involved_in
  review:
    summary: cholesterol homeostasis is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: This process falls within APOE's core role in lipid transport, lipoprotein particle 
      metabolism, and lipid homeostasis.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: IDA
  original_reference_id: PMID:210175
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0051044
    label: positive regulation of membrane protein ectodomain proteolysis
  evidence_type: IDA
  original_reference_id: PMID:15950758
  qualifier: involved_in
  review:
    summary: APOE has credible Alzheimer-relevant evidence for positive regulation of membrane 
      protein ectodomain proteolysis, but this is secondary to its core apolipoprotein 
      lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  evidence_type: IPI
  original_reference_id: PMID:17326667
  qualifier: enables
  review:
    summary: APOE low-density lipoprotein particle receptor binding supports receptor- or 
      proteoglycan-dependent uptake of APOE-containing lipoprotein particles.
    action: ACCEPT
    reason: Receptor and HSPG interactions are central to APOE-mediated lipoprotein clearance and 
      particle uptake.
    supported_by:
    - reference_id: PMID:2762297
      supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis
        of cholesteryl esters contained in lipoproteins that are enriched in apo E.
    - reference_id: PMID:7635945
      supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and 
        its ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
    - reference_id: PMID:23676495
      supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
        mediated by multivalent binding to ApoE and ApoAV.
- term:
    id: GO:0042627
    label: chylomicron
  evidence_type: IDA
  original_reference_id: PMID:8245722
  qualifier: part_of
  review:
    summary: APOE is appropriately localized to chylomicron as a secreted apolipoprotein associated 
      with plasma and tissue lipoprotein particles.
    action: ACCEPT
    reason: Extracellular and lipoprotein-particle component annotations capture APOE's core site of
      action in lipid transport and lipoprotein clearance.
    supported_by:
    - reference_id: PMID:8340399
      supporting_text: These results indicate lipoprotein association modulates the clearance of 
        apoE
    - reference_id: PMID:9488694
      supporting_text: Exogenously applied lipid-free apoE readily bound to the ECM; however, 
        increasing the lipid content decreased its association.
- term:
    id: GO:0007186
    label: G protein-coupled receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:16443932
  qualifier: involved_in
  review:
    summary: G protein-coupled receptor signaling pathway is plausible APOE-associated signaling or 
      regulatory biology, but it is not the core apolipoprotein function.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core because APOE can signal through receptors and alter downstream 
      pathways, but these are context-dependent consequences of APOE-lipoprotein or receptor 
      interactions.
- term:
    id: GO:0033344
    label: cholesterol efflux
  evidence_type: IDA
  original_reference_id: PMID:16443932
  qualifier: involved_in
  review:
    summary: cholesterol efflux is part of APOE's core lipoprotein transport, remodeling, or 
      clearance biology.
    action: ACCEPT
    reason: Cholesterol and phospholipid efflux are well-supported APOE functions in peripheral and 
      CNS-relevant cell systems.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:7972031
  qualifier: enables
  review:
    summary: Generic protein binding annotation for APOE.
    action: MARK_AS_OVER_ANNOTATED
    reason: The underlying interaction may be real, but this term is too generic for APOE; specific 
      receptor binding, lipoprotein particle binding, amyloid-beta binding, tau binding, or 
      lipid-transfer terms are more informative.
- term:
    id: GO:0008289
    label: lipid binding
  evidence_type: IDA
  original_reference_id: PMID:4066713
  qualifier: enables
  review:
    summary: APOE lipid binding is part of its core exchangeable apolipoprotein role in lipid and 
      sterol transport.
    action: ACCEPT
    reason: APOE lipid/phospholipid binding and cholesterol transfer underlie 
      cholesterol/phospholipid efflux and HDL-like particle assembly.
    supported_by:
    - reference_id: PMID:11162594
      supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
        apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
        cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
        cells.
    - reference_id: PMID:17305370
      supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
        necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
    - reference_id: PMID:4066713
      supporting_text: The results are consistent with a model that amphiphilic alpha-helical 
        conformation is responsible both for self-association and surface binding
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:11305869
  qualifier: enables
  review:
    summary: APOE has credible Alzheimer-relevant evidence for amyloid-beta binding, but this is 
      secondary to its core apolipoprotein lipid-transport role.
    action: KEEP_AS_NON_CORE
    reason: Amyloid-related annotations should be retained as disease-relevant non-core biology 
      rather than treated as APOE's primary evolved molecular function.
    supported_by:
    - reference_id: PMID:25207746
      supporting_text: apoE binds primarily to and affects the growth of oligomers that lead to the 
        nuclei required for fibril growth.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:9622609
  qualifier: located_in
  review:
    summary: cytoplasm is retained as APOE-associated contextual biology, not as the core 
      apolipoprotein activity.
    action: KEEP_AS_NON_CORE
    reason: This annotation is not central to APOE lipid transport or lipoprotein clearance but is 
      plausible enough to retain outside the core function set.
- term:
    id: GO:0007271
    label: synaptic transmission, cholinergic
  evidence_type: TAS
  original_reference_id: PMID:9622609
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including synaptic transmission, 
      cholinergic, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0030516
    label: regulation of axon extension
  evidence_type: TAS
  original_reference_id: PMID:9622609
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including regulation of axon extension,
      largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
- term:
    id: GO:0000302
    label: response to reactive oxygen species
  evidence_type: NAS
  original_reference_id: PMID:11743999
  qualifier: involved_in
  review:
    summary: APOE-associated response to reactive oxygen species is secondary vascular, antioxidant,
      or stress-response biology.
    action: KEEP_AS_NON_CORE
    reason: This annotation has plausible experimental support but should not be promoted above 
      APOE's primary role in lipid transport and lipoprotein clearance.
- term:
    id: GO:0007010
    label: cytoskeleton organization
  evidence_type: TAS
  original_reference_id: PMID:9622609
  qualifier: involved_in
  review:
    summary: cytoskeleton organization is retained as non-core APOE-associated biology pending a 
      deeper reference-specific adjudication.
    action: KEEP_AS_NON_CORE
    reason: The annotation is not part of the primary lipid-transport and lipoprotein-clearance 
      function set, but available local evidence was not sufficient to remove it.
- term:
    id: GO:0048168
    label: regulation of neuronal synaptic plasticity
  evidence_type: TAS
  original_reference_id: PMID:9622609
  qualifier: involved_in
  review:
    summary: APOE influences neuronal or synaptic phenotypes including regulation of neuronal 
      synaptic plasticity, largely through CNS lipid transport and receptor-dependent contexts.
    action: KEEP_AS_NON_CORE
    reason: Retain as non-core pleiotropic CNS biology; these annotations describe downstream or 
      cell-context phenotypes rather than APOE's primary apolipoprotein molecular activity.
    supported_by:
    - reference_id: PMID:12042316
      supporting_text: Cholesterol and phospholipids were released into the culture media, resulting
        in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
        associated with apoE and the other with apoJ.
    - reference_id: PMID:24345162
      supporting_text: Brain uptake of [(14) C]-DHA was 24% lower in APOE4 versus APOE2 mice.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by 
    curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary 
    mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using 
    Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11162594
  title: Apolipoprotein specificity for lipid efflux by the human ABCAI transporter.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports APOE as an exchangeable 
      apolipoprotein acceptor for ABCA1-mediated cholesterol and phospholipid 
      efflux.
- id: PMID:11305869
  title: Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta 
    aggregation.
  findings: []
- id: PMID:11743999
  title: Apolipoprotein E modulates Alzheimer's Abeta(1-42)-induced oxidative damage to synaptosomes
    in an allele-specific manner.
  findings: []
- id: PMID:12042316
  title: Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human
    ApoE3 and ApoE4 knock-in mice.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports APOE-containing HDL-like particle 
      release from astrocytes and APOE isoform effects on cholesterol release.
- id: PMID:12401887
  title: Evidence for differential effects of apoE3 and apoE4 on HDL metabolism.
  findings: []
- id: PMID:12950167
  title: 'Domains of apoE required for binding to apoE receptor 2 and to phospholipids: implications for
    the functions of apoE in the brain.'
  findings: []
- id: PMID:1384047
  title: 'Rabbit very low density lipoprotein receptor: a low density lipoprotein receptor-like protein
    with distinct ligand specificity.'
  findings: []
- id: PMID:14754908
  title: 'Molecular interactions between apoE and ABCA1: impact on apoE lipidation.'
  findings: []
- id: PMID:15182176
  title: Two apolipoprotein E mimetic peptides, ApoE(130-149) and ApoE(141-155)2, bind to LRP1.
  findings: []
- id: PMID:1530612
  title: 'Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3'
  findings: []
- id: PMID:15615705
  title: CLAC binds to amyloid beta peptides through the positively charged amino acid cluster 
    within the collagenous domain 1 and inhibits formation of amyloid fibrils.
  findings: []
- id: PMID:15654758
  title: Apolipoprotein E is the major physiological activator of lecithin-cholesterol 
    acyltransferase (LCAT) on apolipoprotein B lipoproteins.
  findings: []
- id: PMID:15950758
  title: Regulation of ApoE receptor proteolysis by ligand binding.
  findings: []
- id: PMID:16273551
  title: Blockade of nicotinic acetylcholine receptors suppresses hippocampal long-term potentiation
    in wild-type but not ApoE4 targeted replacement mice.
  findings: []
- id: PMID:16443932
  title: Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter.
  findings: []
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by proteomics.'
  findings: []
- id: PMID:16805831
  title: Inhibition of the canonical Wnt signaling pathway by apolipoprotein E4 in PC12 cells.
  findings: []
- id: PMID:16935699
  title: Apolipoprotein E enrichment of immuno-separated chylomicron and chylomicron remnants 
    following saturated fatty acids.
  findings: []
- id: PMID:17116874
  title: Blocking the apolipoprotein E/amyloid-beta interaction as a potential therapeutic approach 
    for Alzheimer's disease.
  findings: []
- id: PMID:17154273
  title: Proteomic analysis of human very low-density lipoprotein by two-dimensional gel 
    electrophoresis and MALDI-TOF/TOF.
  findings: []
- id: PMID:17305370
  title: The C-terminal lipid-binding domain of apolipoprotein E is a highly efficient mediator of 
    ABCA1-dependent cholesterol efflux that promotes the assembly of high-density lipoproteins.
  findings: []
- id: PMID:17326667
  title: Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene 
    family.
  findings: []
- id: PMID:17336988
  title: Fractionation of cholesteryl ester rich intermediate density lipoprotein subpopulations by 
    chondroitin sulphate.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:1911868
  title: Effects of exogenous apo E-3 and of cholesterol-enriched meals on the cellular metabolism 
    of human chylomicrons and their remnants.
  findings: []
- id: PMID:1917954
  title: Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular 
    metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor 
    pathway.
  findings: []
- id: PMID:19758344
  title: Haptoglobin binds the antiatherogenic protein apolipoprotein E - impairment of 
    apolipoprotein E stimulation of both lecithin:cholesterol acyltransferase activity and 
    cholesterol uptake by hepatocytes.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20005821
  title: Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid 
    deposition and increases extracellular A beta clearance.
  findings: []
- id: PMID:20030366
  title: 'Decoding of lipoprotein-receptor interactions: properties of ligand binding modules governing
    interactions with apolipoprotein E.'
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications 
    for exosome biogenesis.
  findings: []
- id: PMID:20551380
  title: Proteomics characterization of extracellular space components in the human aorta.
  findings: []
- id: PMID:210174
  title: Apoprotein (E--A-II) complex of human plasma lipoproteins. I. Characterization of this 
    mixed disulfide and its identification in a high density lipoprotein subfraction.
  findings: []
- id: PMID:210175
  title: Apoprotein (E--A-II) complex of human plasma lipoproteins. II. Receptor binding activity of
    a high density lipoprotein subfraction modulated by the apo(E--A-II) complex.
  findings: []
- id: PMID:21163940
  title: Interactome mapping suggests new mechanistic details underlying Alzheimer's disease.
  findings: []
- id: PMID:21593558
  title: The impact of a novel apolipoprotein E and amyloid-β protein precursor-interacting protein 
    on the production of amyloid-β.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:22138302
  title: Preferential interactions between ApoE-containing lipoproteins and Aβ revealed by a 
    detection method that combines size exclusion chromatography with non-reducing gel-shift.
  findings: []
- id: PMID:22383525
  title: Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Aβ 
    uptake and degradation by astrocytes.
  findings: []
- id: PMID:22516433
  title: Proteomic analysis of microvesicles from plasma of healthy donors reveals high individual 
    variability.
  findings: []
- id: PMID:22528093
  title: Search for amyloid-binding proteins by affinity chromatography.
  findings: []
- id: PMID:22637583
  title: Apolipoprotein E4 effects in Alzheimer's disease are mediated by synaptotoxic oligomeric 
    amyloid-β.
  findings: []
- id: PMID:2280190
  title: 'Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine-arginine
    interchange at residue 112.'
  findings: []
- id: PMID:22988876
  title: The importance of Wnt signalling for neurodegeneration in Parkinson's disease.
  findings: []
- id: PMID:23142051
  title: Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and
    angiogenesis.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in 
    urine.
  findings: []
- id: PMID:23620513
  title: ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in 
    physiological conditions.
  findings: []
- id: PMID:23676495
  title: Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans.
  findings: []
- id: PMID:23845000
  title: Isoform-specific effects of apoE on neurite outgrowth in olfactory epithelium culture.
  findings: []
- id: PMID:24154541
  title: Human APOE genotype affects intraneuronal Aβ1-42 accumulation in a lentiviral gene transfer
    model.
  findings: []
- id: PMID:24328732
  title: ApoE4 delays dendritic spine formation during neuron development and accelerates loss of 
    mature spines in vitro.
  findings: []
- id: PMID:24345162
  title: Reduction in DHA transport to the brain of mice expressing human APOE4 compared to APOE2.
  findings: []
- id: PMID:24412220
  title: Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory 
    retention and brain ApoE levels in an isoform-dependent manner.
  findings: []
- id: PMID:24446231
  title: Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and 
    microglia in vitro.
  findings: []
- id: PMID:24447298
  title: 'LDL receptor/lipoprotein recognition: endosomal weakening of ApoB and ApoE binding to the convex
    face of the LR5 repeat.'
  findings: []
- id: PMID:24769233
  title: 'Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset.'
  findings: []
- id: PMID:2498325
  title: Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194.
  findings: []
- id: PMID:25015123
  title: Apolipoprotein E isoform-specific effects on lipoprotein receptor processing.
  findings: []
- id: PMID:25122793
  title: Apolipoprotein E likely contributes to a maturation step of infectious hepatitis C virus 
    particles and interacts with viral envelope glycoproteins.
  findings: []
- id: PMID:25207746
  title: The binding of apolipoprotein E to oligomers and fibrils of amyloid-β alters the kinetics 
    of amyloid aggregation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full-text record supports APOE binding to amyloid-beta
      oligomers/fibrils and modulation of aggregation kinetics; this supports
      non-core Alzheimer-context annotations.
- id: PMID:26387950
  title: Apolipoprotein E Regulates Amyloid Formation within Endosomes of Pigment Cells.
  findings: []
- id: PMID:26468283
  title: Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement 
    Regulation on High Density Lipoprotein Particles.
  findings: []
- id: PMID:26921451
  title: Effects of different isoforms of apoE on aggregation of the α-synuclein protein implicated 
    in Parkinson's disease.
  findings: []
- id: PMID:27044754
  title: FRMD4A-cytohesin signaling modulates the cellular release of tau.
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose
    veins.'
  findings: []
- id: PMID:2745454
  title: Apolipoprotein E mediates binding of normal very low density lipoprotein to heparin but is 
    not required for high affinity receptor binding.
  findings: []
- id: PMID:27477018
  title: TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake
    of Amyloid-Beta by Microglia.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports APOE-containing lipoproteins as 
      TREM2 ligands and links APOE to microglial uptake of amyloid-lipoprotein
      complexes.
- id: PMID:27559042
  title: Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial 
    Fibrillation.
  findings: []
- id: PMID:2762297
  title: Low density lipoprotein receptor-related protein mediates uptake of cholesteryl esters 
    derived from apoprotein E-enriched lipoproteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract supports receptor-mediated uptake and 
      lysosomal processing of apoE-enriched lipoprotein particles through LRP.
- id: PMID:28111074
  title: ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Aβ Secretion.
  findings: []
- id: PMID:28164773
  title: Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:28887769
  title: α-Synuclein Interacts with Lipoproteins in Plasma.
  findings: []
- id: PMID:29507344
  title: Effect of human very low-density lipoproteins on cardiotrophin-like cytokine factor 1 
    (CLCF1) activity.
  findings: []
- id: PMID:30333625
  title: LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration.
  findings: []
- id: PMID:30341064
  title: High-affinity interactions and signal transduction between Aβ oligomers and TREM2.
  findings: []
- id: PMID:30448281
  title: Soluble LR11 competes with amyloid β in binding to cerebrospinal fluid-high-density 
    lipoprotein.
  findings: []
- id: PMID:31270237
  title: α-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from 
    Parkinson's disease patients.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers 
    Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:3771793
  title: Familial apolipoprotein E deficiency.
  findings: []
- id: PMID:4066713
  title: Behavior of human apolipoprotein E in aqueous solutions and at interfaces.
  findings: []
- id: PMID:7175379
  title: Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE 
    phenotype E2/2.
  findings: []
- id: PMID:7566652
  title: ApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation.
  findings: []
- id: PMID:7592957
  title: Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells 
    produces differential effects on neurite outgrowth.
  findings: []
- id: PMID:7635945
  title: Dominant expression of type III hyperlipoproteinemia. Pathophysiological insights derived 
    from the structural and kinetic characteristics of ApoE-1 (Lys146-->Glu).
  findings: []
- id: PMID:7683668
  title: Role of heparan sulfate proteoglycans in the binding and uptake of apolipoprotein 
    E-enriched remnant lipoproteins by cultured cells.
  findings: []
- id: PMID:7972031
  title: 'Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications
    for Alzheimer disease.'
  findings: []
- id: PMID:8071364
  title: Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the
    E3 and E4 isoforms.
  findings: []
- id: PMID:8083695
  title: 'Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron
    microscopic study.'
  findings: []
- id: PMID:8089103
  title: Isoform-specific binding of apolipoprotein E to beta-amyloid.
  findings: []
- id: PMID:8127890
  title: A plasma lipoprotein containing only apolipoprotein E and with gamma mobility on 
    electrophoresis releases cholesterol from cells.
  findings: []
- id: PMID:8245722
  title: Identification of disulfide-linked apolipoprotein species in human lipoproteins.
  findings: []
- id: PMID:8300609
  title: Secretion-capture role for apolipoprotein E in remnant lipoprotein metabolism involving 
    cell surface heparan sulfate proteoglycans.
  findings: []
- id: PMID:8340399
  title: Discrete carboxyl-terminal segments of apolipoprotein E mediate lipoprotein association and
    protein oligomerization.
  findings: []
- id: PMID:8939961
  title: Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a 
    ligand for the low density lipoprotein receptor-related protein.
  findings: []
- id: PMID:8995232
  title: Apolipoprotein E inhibits platelet aggregation through the L-arginine:nitric oxide pathway.
    Implications for vascular disease.
  findings: []
- id: PMID:9003062
  title: Characterization of the binding of amyloid-beta peptide to cell culture-derived native 
    apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma.
  findings: []
- id: PMID:9211985
  title: Association of human, rat, and rabbit apolipoprotein E with beta-amyloid.
  findings: []
- id: PMID:9228033
  title: Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein 
    receptor-related protein-2/megalin. A mechanism to prevent pathological accumulation of amyloid 
    beta-peptide.
  findings: []
- id: PMID:9488694
  title: The HepG2 extracellular matrix contains separate heparinase- and lipid-releasable pools of 
    ApoE. Implications for hepatic lipoprotein metabolism.
  findings: []
- id: PMID:9622609
  title: The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease.
  findings: []
- id: PMID:9649566
  title: Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene 
    replacement of mouse Apoe with human Apoe*2.
  findings: []
- id: PMID:9685360
  title: Apolipoprotein E inhibits platelet-derived growth factor-induced vascular smooth muscle 
    cell migration and proliferation by suppressing signal transduction and preventing cell entry to
    G1 phase.
  findings: []
- id: Reactome:R-HSA-174657
  title: chylomicron remnant:apoE complex + LDLR => chylomicron remnant:apoE:LDLR complex
  findings: []
- id: Reactome:R-HSA-174660
  title: nascent chylomicron + spherical HDL:apoC-II:apoC-III:apoE =>spherical  HDL + chylomicron
  findings: []
- id: Reactome:R-HSA-174690
  title: TG-depleted chylomicron + spherical HDL => chylomicron remnant + spherical 
    HDL:apoA-I:apoA-II:apoA-IV:apoC-II:apoC-III
  findings: []
- id: Reactome:R-HSA-174706
  title: chylomicron remnant:apoE:LDLR complex [plasma membrane] => chylomicron remnant:apoE:LDLR 
    complex [clathrin-coated vesicle] (LDLRAP1-dependent)
  findings: []
- id: Reactome:R-HSA-174739
  title: chylomicron remnant + apoE => chylomicron remnant:apoE complex
  findings: []
- id: Reactome:R-HSA-174757
  title: chylomicron => TG-depleted chylomicron + 50 long-chain fatty acids + 50 diacylglycerols
  findings: []
- id: Reactome:R-HSA-2395768
  title: LPL hydrolyses TGs from mature CMs
  findings: []
- id: Reactome:R-HSA-2395784
  title: Nascent CMs transform into mature CMs
  findings: []
- id: Reactome:R-HSA-2404131
  title: LRPs transport extracellular CR:atREs:HSPG:apoE to cytosol
  findings: []
- id: Reactome:R-HSA-2404140
  title: NREH hydrolyses atREs to atROL and FAs
  findings: []
- id: Reactome:R-HSA-2423785
  title: CR:atREs binds apoE and HSPG
  findings: []
- id: Reactome:R-HSA-2429643
  title: NREH hydrolyses atREs (HSPG:apoE) to atROL and FAs
  findings: []
- id: Reactome:R-HSA-2507854
  title: MSR1:ligand (SCARA1:ligand, SR-A:ligand) is endocytosed
  findings: []
- id: Reactome:R-HSA-266303
  title: Spherical HDL binds C and E apolipoproteins
  findings: []
- id: Reactome:R-HSA-8869590
  title: The APOE gene transcription is stimulated by the complex of TFAP2A homodimer and DEK
  findings: []
- id: Reactome:R-HSA-8952289
  title: FAM20C phosphorylates FAM20C substrates
  findings: []
- id: Reactome:R-HSA-9031512
  title: Expression of APOE regulated by NR1H2 or NR1H3
  findings: []
- id: Reactome:R-HSA-9612243
  title: APOE gene transcription is stimulated by ERBB4s80
  findings: []
- id: Reactome:R-HSA-975634
  title: Retinoid metabolism and transport
  findings: []
- id: Reactome:R-HSA-976734
  title: Amyloid fibrils have additional components
  findings: []
core_functions:
- molecular_function:
    id: GO:0120020
    label: cholesterol transfer activity
  description: APOE is an exchangeable apolipoprotein that binds phospholipids and cholesterol and 
    promotes cholesterol/phospholipid efflux and HDL-like particle formation, including 
    ABCA1-dependent lipidation in peripheral cells and CNS-relevant astrocyte contexts.
  directly_involved_in:
  - id: GO:0006869
    label: lipid transport
  - id: GO:0033344
    label: cholesterol efflux
  - id: GO:0033700
    label: phospholipid efflux
  - id: GO:0034380
    label: high-density lipoprotein particle assembly
  - id: GO:0043691
    label: reverse cholesterol transport
  - id: GO:0008203
    label: cholesterol metabolic process
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:11162594
    supporting_text: ApoA-I and all of the other exchangeable apolipoproteins tested (apoA-II, 
      apoA-IV, apoC-I, apoC-II, apoC-III, apoE) showed greater than a threefold increase in 
      cholesterol and phospholipid efflux from ABCAI-GFP transfected cells compared to control 
      cells.
  - reference_id: PMID:17305370
    supporting_text: the CT lipid-binding domain of apoE encompassing amino acids 222-299 is 
      necessary and sufficient for mediating ABCA1 lipid efflux and HDL particle assembly.
  - reference_id: PMID:12042316
    supporting_text: Cholesterol and phospholipids were released into the culture media, resulting 
      in the generation of two types of high density lipoprotein (HDL)-like particles; one was 
      associated with apoE and the other with apoJ.
- molecular_function:
    id: GO:0050750
    label: low-density lipoprotein particle receptor binding
  description: APOE acts as a receptor/proteoglycan ligand on triglyceride-rich and cholesterol-rich
    lipoprotein particles, enabling uptake and clearance of chylomicron remnants, VLDL remnants, 
    IDL/LDL-related particles, and HDL particles by hepatocytes and other cells.
  directly_involved_in:
  - id: GO:0006898
    label: receptor-mediated endocytosis
  - id: GO:0034382
    label: chylomicron remnant clearance
  - id: GO:0034447
    label: very-low-density lipoprotein particle clearance
  - id: GO:0071830
    label: triglyceride-rich lipoprotein particle clearance
  - id: GO:0055090
    label: acylglycerol homeostasis
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:2762297
    supporting_text: We conclude that LRP can mediate the cellular uptake and lysosomal hydrolysis 
      of cholesteryl esters contained in lipoproteins that are enriched in apo E.
  - reference_id: PMID:7635945
    supporting_text: ApoE-1 (Lys146-->Glu) was defective in interacting with LDL receptors, and its 
      ability to displace LDL in an in vitro assay was reduced to 7.7% compared with apoE-3.
  - reference_id: PMID:23676495
    supporting_text: We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and 
      mediated by multivalent binding to ApoE and ApoAV.
  - reference_id: PMID:8340399
    supporting_text: These results indicate lipoprotein association modulates the clearance of apoE
proposed_new_terms: []
suggested_questions:
- question: Which APOE receptor-binding and proteoglycan-binding annotations should be separated by 
    particle class, tissue, and receptor family in normal in-vivo lipid clearance?
  experts:
  - lipoprotein metabolism curators
  - cardiovascular lipid biology experts
- question: Which CNS APOE phenotypes are direct consequences of astrocyte/glial lipid transport 
    versus downstream effects of amyloid, tau, inflammatory, or synaptic disease-model systems?
  experts:
  - neurobiology curators
  - Alzheimer lipid biology experts
- question: How should APOE amyloid-beta, tau, TREM2/LILRB4, and extracellular-vesicle annotations 
    be represented without obscuring the core apolipoprotein lipid-transfer function?
  experts:
  - GO amyloid biology curators
  - microglial lipid signaling experts
suggested_experiments:
- description: Use endogenous APOE isoform knock-in hepatocyte, macrophage, astrocyte, and 
    microglial systems with particle-resolved lipidomics to distinguish APOE-dependent lipid efflux,
    particle assembly, and particle clearance outputs.
  hypothesis: APOE core functions differ by cell type and lipoprotein particle class, but converge 
    on lipid loading, receptor/proteoglycan binding, and clearance.
  experiment_type: endogenous isoform knock-in lipidomics and particle proteomics
- description: Quantify APOE-containing extracellular vesicle and multivesicular-body pools 
    separately from classical lipoprotein particles under baseline physiological conditions.
  hypothesis: APOE vesicle localization is a real but context-specific pool that should be curated 
    separately from bulk secreted lipoprotein-particle APOE.
  experiment_type: subcellular fractionation and vesicle proteomics
- description: Compare amyloid-beta, tau, and TREM2/LILRB4 binding assays using lipid-free APOE, 
    defined lipidated particles, and endogenous CNS APOE particles.
  hypothesis: Many disease-relevant APOE interactions depend on lipidation state and particle 
    context, and should not be collapsed into generic protein binding.
  experiment_type: particle-defined binding and uptake assays

Gene Description

Existing Annotations Review

Core Functions

APOE is an exchangeable apolipoprotein that binds phospholipids and cholesterol and promotes cholesterol/phospholipid efflux and HDL-like particle formation, including ABCA1-dependent lipidation in peripheral cells and CNS-relevant astrocyte contexts.

APOE acts as a receptor/proteoglycan ligand on triglyceride-rich and cholesterol-rich lipoprotein particles, enabling uptake and clearance of chylomicron remnants, VLDL remnants, IDL/LDL-related particles, and HDL particles by hepatocytes and other cells.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

APOE Notes

2026-06-19

2026-06-20 second-pass audit

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