APP (amyloid-beta precursor protein) is a type I transmembrane glycoprotein of the APP family. Full-length APP acts at the neuronal cell surface as a receptor and adhesion molecule: trans-dimerization of its ectodomain between neighbouring cells promotes synaptogenesis, and it supports neurite outgrowth and axonogenesis, partly through binding heparin and collagen in the extracellular matrix. It traffics from the ER and Golgi to the plasma membrane and is rapidly internalized through clathrin-coated pits into endosomes. Sequential proteolysis by alpha- or beta-secretase and gamma-secretase releases a soluble ectodomain, the amyloid-beta peptides and the APP intracellular domain (AICD); the AICD binds PTB-domain adaptors such as FE65/APBB1 through its YENPTY motif and can enter the nucleus to promote transcription. Isoforms containing the Kunitz domain (APP751/770) inhibit serine proteases. Amyloid-beta peptides bind copper and zinc and aggregate into oligomers and fibrils that activate microglia and astrocytes and impair synaptic plasticity in Alzheimer disease. The donkey protein A0A9L0JJJ9 is a full-length 770-residue product, the KPI-containing APP770 form, 97.9% identical to human APP with identical Kunitz, E2, amyloid-beta and intracellular regions, and it belongs to the vertebrate APP orthology group (PANTHER subfamily PTHR23103:SF7).
Summary: Microglial cell activation (Compara from human IGI, PMID:15457210).
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
TLR2 deficiency reduced AΞ²42-triggered inflammatory activation but enhanced AΞ² phagocytosis in cultured microglia and macrophages
GO:0002265 astrocyte activation involved in immune response
IEA GO_REF:0000107
UNDECIDED
Summary: Astrocyte activation involved in immune response (Compara from human IGI, PMID:23152628).
Reason: Amyloid-beta acts on glia, so an astrocyte role is plausible, but the only donor (human IGI, PMID:23152628) is cached abstract-only and its abstract concerns LRP1-mediated amyloid-beta clearance by brain vascular smooth muscle cells; it does not mention astrocytes. The human UniProt record names mononuclear phagocytes, not astrocytes. No quotable evidence for astrocyte activation was found, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Endopeptidase inhibitor activity (UniRule-based transfer). True for KPI-containing isoforms, but entailed by the accepted serine-type endopeptidase inhibitor activity.
Reason: Serine-type endopeptidase inhibitor activity (GO:0004867) is accepted in this review and is the informative child.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
isoforms that contain the BPTI domain possess protease inhibitor
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
human region 291-341: 51 of 51 residues aligned, 51 identical
Summary: Serine-type endopeptidase inhibitor activity (combined IEA). The donkey model is the KPI-containing APP770 isoform, and human KPI-containing isoforms inhibit serine proteases (human IDA, PMID:10652580).
Reason: The BPTI/Kunitz domain is 100% identical to human; the activity is isoform-dependent (absent from APP695) but present in this gene product.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
isoforms that contain the BPTI domain possess protease inhibitor
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
human region 291-341: 51 of 51 residues aligned, 51 identical
Summary: Signaling receptor binding (combined IEA). APP and its fragments bind several receptors (human IPI rows).
Reason: True but a broad binding term; the informative activity is captured by signaling receptor activator activity. The donkey sequence is 97.9% identical to human APP770.
Summary: Nuclear envelope lumen (Compara from a single human IDA, PMID:21989385); not verifiable from available text.
Reason: Nuclear envelope lumen is transferred from a single human IDA (PMID:21989385, a kinetic model of amyloidogenic processing and SORLA). The cached abstract does not describe this localization, and no curated UniProt location statement supports it. A soluble ectodomain or amyloid-beta in the perinuclear cisterna is possible, since that space is continuous with the ER lumen, but this cannot be verified here.
Summary: Plasma membrane (combined IEA). APP is a single-pass type I cell-surface protein (human EXP).
Reason: Core location of the full-length receptor.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Summary: Signal transduction (inferred from the receptor activator activity, GO_REF:0000108). APP acts as a cell-surface receptor coupled to adaptor and G(o) pathways.
Reason: True in a general sense; broad parent of the specific APP-dependent signalling processes, kept as non-core.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Summary: Axonogenesis (TreeGrafter). APP functions on the neuronal surface in neurite growth and axonogenesis (mouse IMP, PMID:9390996).
Reason: Core physiological function of full-length APP, conserved in the APP family; consistent with the human review.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Summary: Central nervous system development (TreeGrafter).
Reason: Broad developmental process; APP family members contribute to CNS development, but the informative processes are axonogenesis and synapse organization.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Summary: Learning or memory (Compara from human AD-model IGI/IMP rows). Organism-level phenotype of amyloid-beta toxicity.
Reason: Every human donor for this term is an Alzheimer-model study in which overexpressed mutant APP, or the amyloid-beta it produces, impairs spatial learning and memory and a receptor knockout (RAGE, PrP, alpha7 nAChR, LilrB2, EphB2) modifies the deficit. That is a toxic gain-of-function phenotype at organism level, not evidence that APP performs part of learning or memory. APP does act at synapses (synapse organization, presynapse assembly), and those cellular roles are accepted separately.
Summary: Learning (Compara from a human IMP in the PDAPP plaque model). Organism-level disease phenotype.
Reason: The single human donor (PMID:11140684) shows that PDAPP mice, which overexpress mutant human APP, develop an age-related learning deficit that correlates with plaque burden. Impaired learning caused by a pathogenic transgene is not participation of APP in learning.
Summary: Heparin binding (combined IEA). APP binds heparin and collagen to regulate neurite outgrowth; heparin binding also promotes APP dimerization.
Reason: Well-characterized ectodomain property conserved in the 97.9%-identical donkey protein (E1 and E2 heparin-binding domains conserved).
Supporting Evidence:
file:human/APP/APP-uniprot.txt
extracellular matrix such as heparin and collagen I and IV.
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
E1 domain (28-189) 156/162 identical
GO:0008285 negative regulation of cell population proliferation
IEA GO_REF:0000107
UNDECIDED
Summary: Negative regulation of cell population proliferation (Compara from one human IDA on antimicrobial amyloid peptides).
Reason: The only donor is a human IDA (assigned by UniProt) citing PMID:22944668, whose cached abstract-only text is about antimicrobial activity and membrane disruption by aggregates of human islet amyloid polypeptide (IAPP, amylin). It never mentions APP or amyloid-beta and contains no proliferation assay, and killing bacteria would not be a regulatory role in the proliferation of the organism's own cells in any case. Unless the full text also assays amyloid-beta, the upstream row is on the wrong gene product or keyed to the wrong paper; this is recorded as a source defect. Nothing else supports an antiproliferative role of APP, so the transferred row is left undecided.
Summary: Positive regulation of gene expression (Compara from human IGI, PMID:22198949).
Reason: The donor (human IGI, PMID:22198949) is cached abstract-only. Its abstract shows TLR2-dependent inflammatory activation of microglia by Abeta42 and a shift from M1 to M2 activation, but it names no gene whose expression goes up or down, so neither this positive row nor the negative-regulation row (GO:0010629) can be checked against the available text. One sentence cannot support both directions, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Negative regulation of gene expression (Compara from human IGI, PMID:22198949).
Reason: The donor (human IGI, PMID:22198949) is cached abstract-only. Its abstract shows TLR2-dependent inflammatory activation of microglia by Abeta42 and a shift from M1 to M2 activation, but it names no gene whose expression goes up or down, so neither this negative row nor the positive-regulation row (GO:0010628) can be checked against the available text. One sentence cannot support both directions, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Microglia development (Compara from a human IGI on TLR2-dependent microglial activation by AΞ²42).
Reason: The single human donor (IGI, PMID:22198949) measures Abeta42-triggered inflammatory activation of microglia through TLR2. Activation is already captured by the microglial cell activation row; amyloid-beta does not take part in the development of microglia.
Summary: Enzyme binding (Compara from human IPI). APP binds secretases and kinases.
Reason: True: human APP binds enzymes, including the gamma-secretase catalytic subunit PSEN1 (directly, PMID:30630874) and insulin-degrading enzyme IDE (PMID:17051221), but enzyme binding is an uninformative term. The Compara donor (PMID:17112471) is cached abstract-only and reports ADAM19 alpha-secretase cleavage of APP, a processing outcome rather than a binding assay, so it is not cited.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30630874).
Summary: Growth cone (SubCell mapping). Thr-743-phosphorylated APP is concentrated in growth cones during neuronal differentiation (rat IDA PMID:12843239; human PMID:10341243).
Reason: Consistent with APP's role in neurite growth.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
Summary: Signaling receptor activator activity (TreeGrafter). The APP ectodomain acts as a ligand/receptor at the neuronal surface (mouse IDA, PMID:11316806).
Reason: Consistent with the human review (accepted, core) and with APP's receptor-like surface function; PAINT node placement in the APP family is sound for this ortholog.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
aligned pairs 770; identical 754; identity over aligned pairs 97.92%
Summary: Early endosome membrane (Compara from human IDA, PMID:16174740).
Reason: Human APP is in early endosomes (curated UniProt location, PMID:20580937) and is a single-pass type I membrane protein, so its early-endosome pool is in the organelle membrane. The Compara donor (PMID:16174740) is cached abstract-only and says only endosomal and Golgi compartments, so it is not cited.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Early endosome {ECO:0000269|PubMed:20580937}.
file:human/APP/APP-uniprot.txt
Single-pass type I membrane protein
GO:0032224 positive regulation of synaptic transmission, cholinergic
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of synaptic transmission, cholinergic (Compara from human IDA, PMID:33239400).
Reason: Amyloid-beta acting on nicotinic acetylcholine receptors; a fragment activity, kept as non-core.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Amyloid-beta protein 42 binds CHRNA7 in hippocampal neurons.
We used single-channel electrophysiology to show that oAΞ²42 activates both homomeric Ξ±7- and heteromeric Ξ±7Ξ²2-nAChR subtypes
GO:0032722 positive regulation of chemokine production
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of chemokine production (Compara from human IGI, PMID:22406537).
Reason: Amyloid-beta is pro-inflammatory, but the only donor (human IGI, PMID:22406537) is cached abstract-only and its abstract reports that a RAGE blocker suppresses microglial activation and the neuroinflammatory response without naming any chemokine. The cytokine-specific evidence is presumably in the full text, which could not be read, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
GO:0032731 positive regulation of interleukin-1 beta production
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of interleukin-1 beta production (Compara from human IGI, PMID:22406537).
Reason: Amyloid-beta is pro-inflammatory, but the only donor (human IGI, PMID:22406537) is cached abstract-only and its abstract reports that a RAGE blocker suppresses microglial activation and the neuroinflammatory response without naming interleukin-1 beta. The human UniProt line on inflammatory responses is generic. The cytokine-specific evidence is presumably in the full text, which could not be read, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
GO:0032755 positive regulation of interleukin-6 production
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of interleukin-6 production (Compara from human IGI, PMID:22406537).
Reason: Amyloid-beta is pro-inflammatory, but the only donor (human IGI, PMID:22406537) is cached abstract-only and its abstract reports that a RAGE blocker suppresses microglial activation and the neuroinflammatory response without naming interleukin-6. The cytokine-specific evidence is presumably in the full text, which could not be read, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
GO:0032760 positive regulation of tumor necrosis factor production
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of tumor necrosis factor production (Compara from human IGI).
Reason: Amyloid-beta is pro-inflammatory, but the only donor (human IGI, PMID:22198949) is cached abstract-only and its abstract reports TLR2-dependent inflammatory activation of microglia without naming tumor necrosis factor. The cytokine-specific evidence is presumably in the full text, which could not be read, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Identical protein binding (Compara from human IPI). APP homodimerizes, enhanced by Cu2+ and heparin; trans-dimerization drives synaptogenesis.
Reason: Homodimerization is a characterized, functionally relevant property of APP; amyloid-beta self-association also contributes to these IPI rows.
Summary: Dendritic spine (Compara from human IDA, PMID:11988176).
Reason: Dendritic APP is documented (accepted dendrite row, PMID:23931995), but that evidence does not distinguish spines from shafts. The only donor for the spine-specific location is a human IDA citing PMID:11988176, whose cached abstract-only text concerns the acid-sensing ion channel ASIC and does not mention APP. The sub-dendritic location cannot be checked, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Dendritic shaft (Compara from human IDA, PMID:11988176).
Reason: Dendritic APP is documented (accepted dendrite row, PMID:23931995), but that evidence does not distinguish shafts from spines. The only donor for the shaft-specific location is a human IDA citing PMID:11988176, whose cached abstract-only text concerns the acid-sensing ion channel ASIC and does not mention APP. The sub-dendritic location cannot be checked, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Signaling receptor complex (Compara from human IDA, PMID:23382219).
Reason: The donor (human IDA, PMID:23382219) is cached in full. It is a structural study of cargo recognition by the PX-FERM sorting nexins SNX17, SNX27 and SNX31, in which APP appears only as a previously identified SNX17 cargo; nothing in it places APP in a signalling receptor complex, and no other cached source does. This is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Membrane raft (combined IEA). APP and amyloid-beta associate with lipid rafts (human IDA, PMID:24499793); amyloidogenic processing is raft-associated.
Reason: Amyloid-beta binds GPC1 in lipid rafts (curated human UniProt function). The Compara donor (PMID:24499793) is cached abstract-only and mentions raft-associated proteins only as a hypothesis, so it is not cited.
Summary: Positive regulation of glycolysis (Compara from a human IGI on microglia of APP/PS1 mice).
Reason: The single human donor (IGI, PMID:29061364) reports that microglia from APP/PS1 transgenic mice are more glycolytic. The transgene creates an amyloid-laden, inflamed brain and the microglia change their metabolism; APP or amyloid-beta is not shown to act on the glycolytic pathway. This is an indirect downstream phenotype.
Summary: Positive regulation of JNK cascade (Compara from human IGI, PMID:23921129).
Reason: The only donor (human IGI, PMID:23921129) is cached abstract-only; its abstract reports FcgammaRIIb-mediated ER stress, caspase-12 activation, inhibition of long-term potentiation and memory impairment by amyloid-beta, but does not mention JNK. No cached source states that APP or amyloid-beta activates the JNK cascade (the human record reports binding of the JNK scaffold MAPK8IP1, which is not activation), so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Transition metal ion binding (InterPro2GO, copper-binding domain). The E1 copper-binding subdomain and amyloid-beta peptides bind copper, zinc and iron.
Reason: Supported for the human protein and its peptides; the donkey CuBD-containing E1 domain is conserved (156/162) and amyloid-beta is identical.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Amyloid-beta peptides are lipophilic metal chelators with
file:human/APP/APP-uniprot.txt
Bind transient metals such as copper, zinc and
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
E1 domain (28-189) 156/162 identical
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
amyloid-beta 1-42 (672-713) 42/42 identical, so the donkey peptide has the human-type sequence
Summary: Receptor ligand activity (Compara from a human IDA in which amyloid-beta contributes to ligand activity, PMID:33239400).
Reason: The donor annotation describes the amyloid-beta peptide acting on a receptor; a fragment activity, kept as non-core. Signaling receptor activator activity is accepted as the general full-length function.
Summary: Astrocyte activation (Compara from human IGI, PMID:15457210).
Reason: Amyloid-beta acts on glia, so an astrocyte role is plausible, but the only donor (human IGI, PMID:15457210) is cached abstract-only and its abstract reports RAGE-dependent neuronal and behavioural effects of amyloid-beta in transgenic mice without mentioning astrocytes. The human UniProt record names mononuclear phagocytes, not astrocytes. No quotable evidence for astrocyte activation was found, so this is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
GO:0048169 regulation of long-term neuronal synaptic plasticity
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Regulation of long-term neuronal synaptic plasticity (Compara from human IGI, PMID:23921129).
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
Summary: Perinuclear region of cytoplasm (Compara from human IDA). APP colocalizes with SORL1 in perinuclear vesicular compartments.
Reason: Experimentally supported.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Colocalizes with SORL1 in a vesicular pattern in cytoplasm and perinuclear regions.
GO:0050729 positive regulation of inflammatory response
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of inflammatory response (Compara from human IMP, PMID:29961672). Amyloid-beta 42 can activate phagocytes and elicit inflammatory responses.
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
BACE1 is required for the cleavage of amyloid precursor protein (APP) to generate AΞ², which stimulates the nuclear transcription factor ΞΊB (NF-ΞΊB) signaling, leading to the secretion of inflammatory cytokines.
expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons
GO:0050850 positive regulation of calcium-mediated signaling
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of calcium-mediated signaling (Compara from human IGI, PMID:22500019).
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
AΞ²1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca(2+)
GO:0051246 regulation of protein metabolic process
IEA GO_REF:0000117
MARK AS OVER ANNOTATED
Summary: Regulation of protein metabolic process (ARBA). Very broad regulatory term.
Reason: Uninformative over-generalization; consistent with the human review.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
GO:0051247 positive regulation of protein metabolic process
IEA GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Positive regulation of protein metabolic process (Compara from human IMP, PMID:11404397).
Reason: Very broad term for an indirect effect; consistent with the human review.
Summary: PTB domain binding (Compara from human IPI). The cytoplasmic YENPTY motif binds PTB/PID domains of APBB, APBA, DAB1, NUMB and SHC1.
Reason: A specific, well-characterized interaction that mediates APP's adaptor-dependent signalling and trafficking; the motif is identical in donkey.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
SUBUNIT: Binds, via its C-terminus, to the PID domain of several
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
transmembrane region and intracellular domain (700-770) identical, including the YENPTY motif
GO:0070374 positive regulation of ERK1 and ERK2 cascade
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Positive regulation of ERK1 and ERK2 cascade (Compara from human IGI, PMID:15457210).
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
early AD etiology involves chronic activation of the ERK MAPK cascade as a consequence of elevated AΞ² binding to and activating this signaling cascade via Ξ±7 nAChRs
GO:0098815 modulation of excitatory postsynaptic potential
IEA GO_REF:0000107
UNDECIDED
Summary: Modulation of excitatory postsynaptic potential (Compara from human IGI, PMID:20974225).
Reason: The only donor (human IGI, PMID:20974225) is cached abstract-only; its abstract measures agonist-enhanced long-term potentiation and alpha7 nAChR ligand binding in APPswe/PS1dE9 hippocampal slices but reports no excitatory postsynaptic potential measurement. This is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Secretory vesicle (ARBA). APP accumulates in secretory transport vesicles leaving the late Golgi; it is also found in neuronal dense core vesicles (rat IDA).
Reason: Supported by the human trafficking data and rat dense-core vesicle localization.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
secretory transport vesicles leaving the late Golgi compartment and
Summary: Amyloid-beta complex (Compara from human IDA). Amyloid-beta peptides form oligomeric complexes.
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
Supporting Evidence:
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
amyloid-beta 1-42 (672-713) 42/42 identical, so the donkey peptide has the human-type sequence
Summary: Molecular function activator activity (ARBA). A very general term with no specific activated activity.
Reason: Uninformative; consistent with the human review, which marks the same ARBA row as over-annotated.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
GO:0150003 regulation of spontaneous synaptic transmission
IEA GO_REF:0000107
UNDECIDED
Summary: Regulation of spontaneous synaptic transmission (Compara from human IGI, PMID:15457210).
Reason: The only donor (human IGI, PMID:15457210) is cached abstract-only; its abstract reports spatial learning and memory and markers of synaptic plasticity in mutant-APP/RAGE transgenic mice, with no measurement of spontaneous synaptic transmission. This is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
GO:1900272 negative regulation of long-term synaptic potentiation
IEA GO_REF:0000107
KEEP AS NON CORE
Summary: Negative regulation of long-term synaptic potentiation (Compara from human IGI). Amyloid-beta oligomers inhibit LTP.
Reason: This is an effect of the amyloid-beta fragment (largely from Abeta/APP-mutant or IGI studies in human or mouse) rather than a physiological core function of full-length APP; kept as non-core. The donkey amyloid-beta sequence is identical to human.
Fcgr2b deficiency ameliorated AΞ²-induced inhibition of long-term potentiation
GO:1900273 positive regulation of long-term synaptic potentiation
IEA GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Positive regulation of long-term synaptic potentiation (Compara from a human IGI in which the APP transgene prevents agonist-enhanced LTP).
Reason: The single human donor (IGI, PMID:20974225) shows that an alpha7 nAChR agonist enhances LTP in wild-type slices but not in APPswe/PS1dE9 slices: the APP transgene blocks a potentiation, which if anything argues the opposite direction. The donkey row also contradicts the retained negative regulation of long-term synaptic potentiation. A physiological LTP-promoting role of secreted APP-alpha may exist but is not what this transfer rests on.
in the Tg mice the application of SSR180711 did not result in an increase in LTP beyond control levels
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of non-canonical NF-kappaB signal transduction (Compara from human IGI, PMID:15457210).
Reason: The only donor (human IGI, PMID:15457210) is cached abstract-only; its abstract describes RAGE as a signal-transducing acceptor for amyloid-beta but does not mention NF-kappaB, let alone the non-canonical pathway. This is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Cellular response to amyloid-beta (Compara from human IDA, PMID:29518356).
Reason: The donor (human IDA, PMID:29518356) is cached abstract-only; its abstract shows that TREM2 binds amyloid-beta oligomers and mediates the microglial response to them. The responding entity there is TREM2-expressing microglia, and the abstract does not show APP taking part in the response. This is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule.
GO:1905908 positive regulation of amyloid fibril formation
IEA GO_REF:0000107
UNDECIDED
Summary: Positive regulation of amyloid fibril formation (Compara from human IMP, PMID:19660551).
Reason: The only donor (human IMP, PMID:19660551) is cached abstract-only and characterises amyloid-beta monomers, dimers, oligomers and insoluble aggregates in J20 APP-transgenic mice; it does not test whether APP regulates fibril formation. Fibril formation by the peptide itself is covered by the amyloid fibril formation row. The regulatory claim is left undecided rather than supported by a quote that does not state it (2026-10-23 re-review).
Summary: Amyloid fibril formation (Compara from human EXP, PMID:26138908). Amyloid-beta peptides themselves assemble into fibrils.
Reason: The peptide performs the assembly, so the gene product participates; pathological process of a fragment, kept as non-core. Donkey amyloid-beta is identical to human.
Supporting Evidence:
file:EQUAS/APP/APP-bioinformatics/RESULTS.md
amyloid-beta 1-42 (672-713) 42/42 identical, so the donkey peptide has the human-type sequence
Summary: Neuron projection maintenance (Compara from a human IGI in which the APP transgene causes axonal degeneration).
Reason: The single human donor (IGI, PMID:20445063) shows that in APPswe/PSen1dE9 mice the transgene causes 5-HT axonal degeneration and loss of synaptic markers, and that deleting PrP(C) rescues it. Amyloid-beta there destroys neuron projections; it is not shown to maintain them. APP's physiological support of neurite growth is captured by the accepted axonogenesis row.
Supporting Evidence:
file:human/APP/APP-uniprot.txt
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice
GO:2000406 positive regulation of T cell migration
IEA GO_REF:0000107
MARK AS OVER ANNOTATED
Summary: Positive regulation of T cell migration (Compara from a human IMP on AΞ² assemblies in J20 mice).
Reason: The single human donor (IMP, PMID:19660551) characterises amyloid-beta assembly forms in J20 transgenic mice; the cached abstract contains no T-cell migration assay. No other evidence links APP to T-cell migration, and an effect of amyloid deposits on T-cell infiltration would be an indirect disease phenotype.
These data demonstrate the presence of multiple assembly forms of Abeta throughout the life of J20 mice
Core Functions
Neuronal cell-surface receptor and synaptic adhesion protein: the ectodomain trans-dimerizes between neighbouring cells to promote synapse formation, supports neurite growth and axonogenesis, and the shed ectodomain and derived peptides act as ligands for cell-surface receptors.
Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis.
file:human/APP/APP-uniprot.txt
molecules on neighboring cells promotes synaptogenesis
Q: Which APP isoforms (APP695 versus KPI-containing APP751/770) are expressed in donkey brain and peripheral tissues, and does the human-type amyloid-beta sequence predispose aged donkeys to amyloid deposition?
Q: Most process annotations transferred to non-human APP orthologs (learning or memory, glial activation, cytokine production, LTP regulation) derive from Alzheimer-model studies of overexpressed mutant APP or applied amyloid-beta acting through receptors such as RAGE, TLR2, PrP and alpha7 nAChR. Should these be captured on the receptors, with amyloid-beta as input, rather than propagated to every APP ortholog as process participation?
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Assessment of 3 ProtNLM2 GO predictions for donkey APP (A0A9L0JJJ9). Extracellular region is already in donkey GOA and correct (CNN). Nucleus is in donkey GOA and correct only for the AICD/gamma-CTF fragment (CNN). Apoptotic process is supported by the pro-apoptotic activity of the caspase-derived C31 peptide and the gamma-secretase-released intracellular domain of human APP, whose sequence donkey shares, and no apoptosis term is in donkey GOA (COR). Non-GO ProtNLM2 output, not scored: subcellular location 'Endosome', which matches the experimentally established endosomal trafficking of human APP.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: Caspase cleavage of human APP releases the C31 peptide, a potent inducer of apoptosis (PMID:10742146), and the gamma-secretase-released intracellular domain acts as a positive regulator of apoptosis (PMID:12214090); Swiss-Prot summarizes both as enhancers of neuronal apoptosis. The donkey intracellular domain, including the caspase site region and YENPTY motif, is identical to human, so the transfer is justified within the APP orthology group. No apoptosis term of any kind is in the donkey GOA record or the donkey gene review (human APP carries apoptotic process as an accepted IEA), so the prediction is novel for this gene. The role is fragment-mediated and non-core, and the evidence is for induction rather than execution, so positive regulation of neuron apoptotic process would be the more precise term.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: After alpha-secretase cleavage the soluble APP ectodomain is released into the extracellular space and amyloid-beta is secreted; human APP has IDA support for the extracellular region. The exact term is already in donkey GOA (combined IEA). Correct but not novel.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-10-14
Review rationale: The gamma-secretase-released C-terminal fragment (AICD) is located in both cytoplasm and nucleus of neurons (human EXP, PMID:11544248). The exact term is already in donkey GOA. Correct for a fragment of the gene product, though not for full-length APP; not novel.