| Substrate | Biological process/function | Consequence of BACE1 cleavage | Evidence |
|---|---|---|---|
| APP (amyloid precursor protein) | Central substrate in the amyloidogenic APP-processing pathway; influences Aβ generation, synaptic biology, and AD pathogenesis | BACE1 performs the initial, rate-limiting β-site cleavage of APP to release sAPPβ and generate membrane-bound C99/CTFβ; γ-secretase then cleaves C99 to produce Aβ peptides. APP/BACE1 colocalization, especially in early endosomes, correlates with increased sAPPβ/Aβ production. BACE1 can also cleave longer Aβ peptides at the β34 site to generate non-toxic Aβ34, indicating an amyloidolytic role in addition to its amyloidogenic role. (pqac-00000005, pqac-00000008, pqac-00000012) | (pqac-00000005, pqac-00000008, pqac-00000012) |
| Neuregulin-1 (NRG1) | Cell growth/differentiation and myelination; implicated in neural development and schizophrenia-related biology | BACE1 cleavage of NRG1 regulates myelination; altered cleavage has been implicated in schizophrenia-related phenotypes. (pqac-00000010) | (pqac-00000010) |
| gp130 (IL6ST) | Coreceptor for IL-6 family cytokine signaling; regulates neuronal IL-6 signaling and neuronal survival | BACE1 directly sheds gp130, reducing membrane-bound gp130 and increasing soluble gp130; this attenuates neuronal IL-6 signaling and affects neuronal survival under growth-factor withdrawal. Human CSF and nonhuman primate pharmacoproteomics support gp130 as an in vivo-relevant BACE1 substrate. (pqac-00000005) | (pqac-00000005) |
| SEZ6 | Neuronal/synaptic function, synaptic connectivity, and motor coordination | BACE1 cleavage sheds SEZ6; reduction of soluble SEZ6 is a strong pharmacodynamic readout of BACE1 inhibition, and loss of processing has been proposed to contribute to seizures, motor deficits, and related phenotypes in BACE1-null mice. (pqac-00000010) | (pqac-00000010) |
| SEZ6L | Neuronal function and synaptic connectivity | Similar to SEZ6, SEZ6L is a neuronal BACE1 substrate whose cleavage contributes to normal synaptic connectivity; impaired shedding may participate in neurological phenotypes seen with BACE1 deficiency. (pqac-00000010) | (pqac-00000010) |
| L1CAM | Axon guidance and neurite outgrowth | BACE1-mediated cleavage sheds L1CAM ectodomain, linking BACE1 activity to axon guidance and neurite extension pathways. (pqac-00000010) | (pqac-00000010) |
| CHL1 | Axon guidance and neurite outgrowth | BACE1 cleavage of CHL1 contributes to pathways controlling axon guidance and neuritic growth; loss of this processing is implicated in developmental wiring defects in BACE1 deficiency. (pqac-00000010) | (pqac-00000010) |
| Jagged 1 (Jag1) | Notch signaling; control of astrogenesis, neurogenesis, hematopoiesis, and cardiovascular development | BACE1 cleavage sheds Jag1 and modulates Jag1-Notch signaling. Reviews note the soluble Jag1 ectodomain likely antagonizes Notch signaling, although its exact function remains incompletely resolved. (pqac-00000010, pqac-00000009) | (pqac-00000010, pqac-00000009) |
| Jagged 2 (Jag2) | Notch signaling, with functions similar to Jag1 | Jag2 is also cleaved by BACE1, though less efficiently than Jag1; cleavage is expected to modulate Jagged-Notch signaling similarly to Jag1. (pqac-00000009) | (pqac-00000009) |
| PSGL-1 (P-selectin glycoprotein ligand-1) | Leukocyte adhesion to endothelial cells during inflammation and tissue injury | BACE1 shedding of PSGL-1 may reduce cell-surface adhesive function; the soluble form may disrupt leukocyte adhesion/diapedesis and thereby alter inflammatory responses. (pqac-00000009, pqac-00000010) | (pqac-00000009, pqac-00000010) |
| Voltage-gated sodium channel β2 subunit (Navβ2) | Sodium channel metabolism and neuronal excitability | BACE1 cleaves Navβ2, linking the protease to sodium-channel processing and neuronal excitability control. This has been proposed as one mechanism underlying electrophysiological abnormalities in BACE1-deficient settings. (pqac-00000010) | (pqac-00000010) |
| NCAM1/NCAM2 | Synapse formation, maturation, and maintenance | Identified as BACE1 substrates in reviews; cleavage connects BACE1 to regulation of synapse development and maintenance. (pqac-00000010) | (pqac-00000010) |
| CACHD1 | Synapse formation/maturation and neuronal connectivity | Listed among BACE1 substrates associated with synaptic biology; cleavage implicates BACE1 in organization and maintenance of neuronal connections. (pqac-00000010) | (pqac-00000010) |
| LRRN1 | Neurite outgrowth | BACE1 cleavage places LRRN1 among substrates through which the protease influences neuritic development and neuronal morphology. (pqac-00000010) | (pqac-00000010) |
| Neurotrimin | Neurite outgrowth and neuronal adhesion-related processes | BACE1-mediated shedding links Neurotrimin to BACE1-dependent control of neurite extension and neural connectivity. (pqac-00000010) | (pqac-00000010) |
| IL-1 receptor type II (IL-1R2) | Immunoregulatory decoy receptor that modulates IL-1/NF-κB inflammatory signaling | Increased BACE1 expression enhances IL-1R2 shedding; soluble IL-1R2 released into the circulation may alter systemic IL-1 activity and inflammatory tone. (pqac-00000009) | (pqac-00000009) |
| Insulin receptor (IR) | Glucose homeostasis and insulin sensitivity | BACE1 cleavage generates soluble IR and reduces functional cell-surface insulin receptor, linking BACE1 activity to impaired insulin signaling and metabolic regulation. (pqac-00000009) | (pqac-00000009) |
| ST6Gal1 (α2,6-sialyltransferase 1) | Terminal N-glycan biosynthesis and processes relevant to leukocyte adhesion/atherosclerosis | BACE1 cleaves ST6Gal1, releasing a soluble form; reviews suggest this may influence leukocyte adhesion/diapedesis and vascular inflammatory biology. (pqac-00000009) | (pqac-00000009) |
| VEGFR1/Flt1 | Negative regulation of VEGF signaling and angiogenesis | BACE1-generated soluble Flt1 acts as a decoy receptor; BACE1 loss reduces sFlt1 and is associated with enhanced angiogenesis/retinal pathology in mouse studies summarized by review literature. (pqac-00000009) | (pqac-00000009) |
| APLP1 / APLP2 | APP-family proteins involved in neuronal biology and broader metabolic regulation | BACE1 cleavage of APP-family proteins is implicated in glucose and insulin homeostasis; review evidence links altered processing to metabolic phenotypes. (pqac-00000009) | (pqac-00000009) |


*Table: This table summarizes major established BACE1 substrates and the biological pathways they regulate, along with the known or proposed consequences of BACE1-mediated shedding. It is useful for functional annotation because it separates APP-centered amyloid biology from broader physiological roles in myelination, synaptic function, inflammation, axon guidance, and metabolism.*