Affinage

BACE1

Beta-secretase 1 · UniProt P56817

Length
501 aa
Mass
55.8 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BACE1 is a membrane-anchored aspartyl protease that functions as the principal neuronal β-secretase and a broad sheddase, governing both amyloidogenic APP processing and the proteolytic regulation of diverse cell-surface and signaling proteins in the nervous system (PMID:22728825, PMID:23931995). Beyond APP, BACE1 cleaves neuregulin-1 to drive ErbB/Akt signaling required for CNS and PNS myelination and remyelination after nerve injury (PMID:17099708, PMID:21576249, PMID:25740511), processes the voltage-gated sodium channel β2-subunit to control Nav1.1 surface expression and sodium current (PMID:17576410), sheds Jagged1 to restrain Notch-dependent astrogenesis and promote neurogenesis (PMID:23831026), and cleaves contactin-2 and a wider set of neuronal substrates implicated in neurite outgrowth and synapse formation (PMID:22728825, PMID:24405708); in non-neuronal cells it cleaves astrocytic insulin receptors to suppress Clusterin-mediated Aβ clearance (PMID:37143090) and processes IL-1R2 and Toll-like receptors in microglia to restrain phagocytic disease-associated microglial signaling (PMID:35857844, PMID:35714196). The enzyme's activity is set by its subcellular itinerary: BACE1 partitions into cholesterol-dependent lipid rafts (PMID:11525745), converges with APP in acidic recycling endosomes upon neuronal activity for amyloidogenic cleavage (PMID:23931995, PMID:26642089), and is sorted for degradation through a C-terminal di-leucine motif to lysosomes and via autophagy (PMID:16033761, PMID:28028177). This trafficking is controlled by an array of factors including the deubiquitinase USP8 (which stabilizes endosomal BACE1 via Lys501) (PMID:27302062), the adaptors GGA3 and AP-2 (PMID:17553422, PMID:32323475), SNX12, Rab35, and Par3/aPKC-mediated Ser498 phosphorylation that promotes PACS1-dependent retrograde transport (PMID:28946017, PMID:22709416, PMID:34876559). BACE1 levels are further tuned transcriptionally through GSK3β/NF-κB and Aβ42-driven JNK/c-jun feedback, and post-translationally by ubiquitination, SUMO1, and S-nitrosylation (PMID:15289451, PMID:23202730, PMID:21371311, PMID:21897006). Functionally, BACE1 is required for synaptic vesicle docking, hippocampal LTP, and learning, acting in part through mGluR1 (PMID:34158621).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2001 High

    Establishing where BACE1 acts within the membrane explained how its activity could be spatially compartmentalized rather than uniformly distributed.

    Evidence Density gradient fractionation and cholesterol depletion across three cell lines

    PMID:11525745

    Open questions at the time
    • Did not connect raft localization to a specific substrate cleavage event
    • Mechanism of raft targeting not defined
  2. 2005 High

    Identifying a di-leucine sorting motif and lysosomal degradation route defined how cells set steady-state BACE1 levels post-translationally.

    Evidence Lysosomal inhibitors plus LL/AA mutagenesis and LAMP2 co-localization in multiple cell types including neurons

    PMID:16033761

    Open questions at the time
    • Did not identify the adaptors recognizing the motif
    • Link to amyloid output not addressed
  3. 2006 High

    Demonstrating BACE1-dependent neuregulin-1 cleavage uncovered a physiological role beyond amyloid, linking the protease to myelination through neuregulin-Akt signaling.

    Evidence Bace1 knockout mice with NRG1 fragment quantification, myelin morphology, and phospho-Akt readouts

    PMID:17099708

    Open questions at the time
    • Cleavage site not mapped in this study
    • Did not distinguish neuronal vs glial source of cleavage
  4. 2007 High

    Showing GGA3 controls BACE1 stability and that BACE1 cleaves the Nav1 β2-subunit extended the enzyme's regulation and substrate repertoire into channel surface control and ischemic stress.

    Evidence GGA3 RNAi with caspase inhibition and AD/ischemia tissue; β2 cleavage with electrophysiology in transgenic mice

    PMID:17553422 PMID:17576410

    Open questions at the time
    • Caspase-cleaved GGA3 species not fully resolved
    • Functional consequence of β2 cleavage in vivo for excitability untested
  5. 2007 Medium

    RTK signaling was shown to acutely enhance BACE1 activity by driving its Rab5/Src-dependent endosomal internalization, tying receptor signaling to amyloidogenesis.

    Evidence EGF/NGF stimulation with Src inhibitors, Src RNAi, and dominant-negative Rab5

    PMID:17325690

    Open questions at the time
    • Direct phosphorylation target linking RTK to BACE1 trafficking not defined
    • Single lab
  6. 2008 High

    Linking BACE1-NRG1 processing to ErbB4-PSD95 signaling connected the protease to synaptic structure and psychiatric-relevant behavior.

    Evidence BACE1 KO mice with behavioral assays, ErbB4-PSD95 Co-IP, spine quantification, and clozapine rescue

    PMID:18385378

    Open questions at the time
    • Only partial pharmacological rescue
    • Causal chain from NRG1 fragment to spine loss not fully isolated
  7. 2009 Medium

    Identifying Aβ42 as the APP derivative driving PS1-mutation-induced BACE1 upregulation revealed a feed-forward link between γ-secretase products and β-secretase levels.

    Evidence PS1 mutant transfection and knock-in mice with γ-secretase inhibition and human FAD tissue

    PMID:19196715

    Open questions at the time
    • Transcriptional vs post-translational basis not separated here
    • Single lab
  8. 2011 Medium

    Multiple regulatory inputs (S1P binding, NO/cGMP and S-nitrosylation, Aβ42/JNK feedback) were resolved, showing BACE1 activity and expression are tuned by lipids, redox state, and product feedback.

    Evidence Direct S1P binding and SphK perturbation; S-nitrosylation biochemistry with PKG inhibition; Aβ42 vs Aβ40 with JNK inhibition; NRG1 cleavage site mapping with myelination co-culture

    PMID:21371311 PMID:21543615 PMID:21576249 PMID:21897006

    Open questions at the time
    • S1P binding site on BACE1 not mapped
    • Concentration thresholds for NO effects from cell culture
    • Each mechanism from a single lab
  9. 2012 High

    Proteome-wide substrate discovery established BACE1 as a major neuronal sheddase with dozens of substrates, while SUMO1, GSK3β/NF-κB, and PKR-eIF2α regulation defined the modification and transcriptional control layers.

    Evidence SPECS proteomics with KO/inhibitor validation; SUMO1 Co-IP and gain/loss; GSK3β isoform-specific inhibition with AD mice; PKR-eIF2α inhibition under oxidative stress; SNX12 Co-IP and trafficking

    PMID:22306812 PMID:22709416 PMID:22728825 PMID:22975420 PMID:23202730

    Open questions at the time
    • Physiological function of most novel substrates not tested
    • Several regulatory pathways validated in single labs
  10. 2013 High

    Live imaging showed APP and BACE1 are normally segregated and converge in recycling endosomes upon neuronal activity, and that BACE1 sheds Jagged1 to restrain Notch-driven astrogenesis, defining both spatial control of amyloidogenesis and a developmental role.

    Evidence Dendritic vesicle live imaging with clathrin inhibition; BACE1 KO/overexpression with Jag1 cleavage and neurogenesis/astrogenesis counts

    PMID:23831026 PMID:23931995

    Open questions at the time
    • Trigger coupling activity to APP rerouting not fully defined
    • Jag1 cleavage site not mapped
  11. 2014 Medium

    Contactin-2 was added as a validated GPI-proximal substrate, and RTN3 was identified as a negative regulator of BACE1 activity, refining substrate scope and endogenous inhibition.

    Evidence Contactin-2 cleavage-site mutagenesis with surface biotinylation; RTN3 KO mice with APP processing and amyloid readouts

    PMID:24405708 PMID:25319692

    Open questions at the time
    • Functional role of soluble contactin-2 not established
    • RTN3-BACE1 inhibitory mechanism not structurally defined
  12. 2015 High

    BACE1-APP interaction was mapped to recycling microdomains and synaptic compartments, the protective Icelandic APP mutation was shown to weaken this interaction, BACE1 was found enriched in synaptic vesicles, and Schwann-cell BACE1 was shown necessary for peripheral remyelination.

    Evidence Fluorescence complementation interaction assay with Icelandic mutant; synaptic vesicle isolation and proximity ligation; sciatic nerve transplantation between BACE1-null and WT

    PMID:25740511 PMID:26296617 PMID:26642089

    Open questions at the time
    • Quantitative contribution of synaptic vs endosomal cleavage to total Aβ unclear
    • Schwann vs axonal NRG1 source contributions not fully apportioned
  13. 2015 Medium

    sAPPα was identified as an endogenous allosteric BACE1 inhibitor whose activity depends on a conformation lost in sAPPβ, revealing a product-level negative feedback on the protease.

    Evidence In vitro BACE1 inhibition with recombinant sAPPα and small-angle X-ray scattering comparison

    PMID:26401691

    Open questions at the time
    • Allosteric site not confirmed by mutagenesis
    • In vivo relevance of inhibition not tested
  14. 2016 Medium

    USP8-mediated deubiquitination at Lys501 and autophagy-lysosomal turnover were defined as opposing arms controlling endosomal BACE1 retention versus degradation.

    Evidence USP8 RNAi with ubiquitination and substrate-processing assays; axonal autophagic vacuole imaging with Snapin overexpression in mutant APP neurons

    PMID:27302062 PMID:28028177

    Open questions at the time
    • E3 ligase acting at Lys501 not identified
    • Each mechanism from single lab
  15. 2017 Medium

    Par3/aPKC phosphorylation of BACE1-Ser498 and p75-mediated co-localization defined phosphorylation-controlled retrograde and amyloidogenic trafficking of BACE1, with reduced Ser498 phosphorylation in AD brain.

    Evidence Par3/aPKC perturbation with phospho-Ser498 analysis and BACE1-PACS1 Co-IP; p75-BACE1 Co-IP with JNK inhibition in cortical neurons

    PMID:28869759 PMID:28946017

    Open questions at the time
    • p75 finding rests on Co-IP and co-localization without reciprocal validation
    • Kinase specificity for Ser498 across pathways not reconciled
  16. 2019 Medium

    MMP13 was shown to control BACE1 translationally via PI3K/eIF4B and the BACE1 5'UTR, adding a translational regulatory node with in vivo amyloid impact.

    Evidence Promoter/5'UTR luciferase screen, eIF4B S422R mutagenesis, 5'UTR deletion, and Mmp13 knockdown in APP/PS1 mice

    PMID:30596903

    Open questions at the time
    • How MMP13 signals to PI3K not defined
    • Single lab
  17. 2020 High

    AP-2 was established as the adaptor routing internalized BACE1 to lysosomes, with genetic rescue confirming BACE1 as the causal amyloidogenic node downstream of AP-2 loss.

    Evidence Conditional AP-2 KO mice and iPSC AD neurons with BACE1-deletion genetic rescue

    PMID:32323475

    Open questions at the time
    • Direct AP-2 recognition motif on BACE1 not defined
    • Relationship to the di-leucine lysosomal motif not reconciled
  18. 2021 High

    BACE1 was shown to be required for synaptic vesicle docking and LTP via mGluR1, and Rab35/OCRL was identified as sorting BACE1 out of the amyloidogenic endosomal route.

    Evidence BACE1 KO and inhibitors with EM vesicle docking, LTP, behavior, and mGluR1 PAM rescue; Rab35 overexpression/knockdown with OCRL/ACAP2 effector studies

    PMID:34158621 PMID:34876559

    Open questions at the time
    • Substrate cleavage event linking BACE1 to vesicle docking not identified
    • How mGluR1 levels depend on BACE1 unclear
  19. 2022 High

    Cell-type-specific deletion revealed microglial BACE1 restrains protective phagocytic and disease-associated microglial programs by cleaving IL-1R2 and Toll-like receptors, repositioning BACE1 as an immune regulator in amyloid clearance.

    Evidence Microglial Bace1 deletion in 5xFAD mice with scRNA-seq, phagocytosis and signaling assays, plaque and LTP readouts

    PMID:35714196 PMID:35857844

    Open questions at the time
    • Direct cleavage of IL-1R2/TLRs not mapped at residue level
    • Translation to non-5xFAD contexts untested
  20. 2023 High

    Astrocytic BACE1 was shown to cleave insulin receptors, and its deletion enhances Clusterin-dependent Aβ clearance, defining a glial substrate-to-clearance axis.

    Evidence Astrocyte-specific Bace1 KO in 5xFAD with scRNA-seq, siRNA, Aβ uptake/degradation, and plaque quantification

    PMID:37143090

    Open questions at the time
    • Insulin receptor cleavage site not mapped
    • Direct Clusterin regulation mechanism downstream of IR signaling not fully defined
  21. 2006 Low

    BACE1 dimerization was proposed as a determinant of catalytic activity, raising the question of how oligomeric state shapes function.

    Evidence Biochemical dimerization and active-site mutagenesis analysis of human brain BACE1

    PMID:17047367

    Open questions at the time
    • Limited mechanistic detail and single study
    • Functional consequence of dimerization not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many trafficking, transcriptional, translational, and post-translational regulators integrate to set BACE1 activity at specific membranes, and which substrate cleavages mediate its non-amyloid synaptic and glial functions, remains unresolved.
  • Substrates linking BACE1 to vesicle docking and LTP unidentified
  • Cleavage sites for several glial/immune substrates unmapped
  • Integration of competing trafficking regulators not reconciled into a unified model

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3
Localization
GO:0005768 endosome 6 GO:0005764 lysosome 3 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2
Partners
APPGGA3NRG1PACS1RTN3SNX12SUMO1USP8

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 BACE1 cleaves neuregulin-1 (NRG1) in the CNS and PNS; genetic deletion of Bace1 in mice causes hypomyelination, delays myelination, reduces myelin sheath thickness, and decreases phosphorylated Akt in myelin-forming cells, with full-length NRG1 accumulating and its cleavage product reduced in null mice, establishing BACE1-mediated NRG1 processing as a regulator of myelination via the neuregulin-Akt signaling pathway. Bace1 knockout mice, western blotting, neurological behavioral assays, immunohistochemistry Nature neuroscience High 17099708
2007 GGA3 (an adaptor protein involved in BACE1 trafficking) controls BACE1 protein stability post-translationally; RNAi depletion of GGA3 elevates BACE1 levels and beta-secretase activity via caspase-activated posttranslational stabilization of BACE1, and GGA3 levels are inversely correlated with BACE1 levels in AD brain and following cerebral ischemia. RNAi knockdown, western blotting, caspase inhibition, AD brain samples, cerebral ischemia model Neuron High 17553422
2007 BACE1 cleaves the voltage-gated sodium channel beta2-subunit (Nav1 β2); BACE1-gamma-secretase sequential cleavage releases the β2 intracellular domain, which increases Nav1.1 alpha-subunit mRNA and protein, but Nav1.1 is retained intracellularly, reducing cell-surface sodium current densities in neuroblastoma cells and hippocampal neurons from BACE1-transgenic mice. BACE1-transgenic mice, neuroblastoma cell overexpression, electrophysiology (sodium current recordings), western blotting, mRNA quantification Nature cell biology High 17576410
2001 BACE1 (Asp2) is compartmentalized into low-buoyant density, non-caveolar lipid rafts; both BACE1 protein and activity co-fractionate with raft markers in three distinct cell lines by detergent and non-detergent methods, and cholesterol depletion abolishes this raft association. Density gradient fractionation (detergent and non-detergent), immunoisolation of caveolin-containing vesicles, cholesterol depletion, enzyme activity assays Current biology High 11525745
2005 BACE1 is degraded via the lysosomal pathway; lysosomal inhibitors (chloroquine, NH4Cl) cause accumulation of BACE1 in LAMP2-positive late endosomal/lysosomal compartments, and the di-leucine motif (LL499/500) in the BACE1 C-terminus is required for efficient lysosomal sorting, as the LL/AA mutant shows impaired co-localization with LAMP2-positive compartments. Lysosomal inhibitor treatment, site-directed mutagenesis (LL/AA), immunofluorescence co-localization, western blotting in multiple cell types including primary neurons The Journal of biological chemistry High 16033761
2004 BACE1 protein is ubiquitinated and degraded via the ubiquitin-proteasome pathway; proteasome inhibition (lactacystin) increases BACE1 protein levels in a time- and dose-dependent manner and elevates APP C99 production and Aβ generation. Proteasome inhibitor treatment (lactacystin), ubiquitination immunoprecipitation, western blotting, Aβ/C99 measurement FASEB journal Medium 15289451
2008 BACE1-dependent NRG1 processing regulates ErbB4 signaling; BACE1-null mice show reduced ErbB4-PSD95 interaction, decreased hippocampal dendritic spine density, and schizophrenia-like behaviors (impaired prepulse inhibition, hyperactivity, cognitive deficits), which are partially rescued by the antipsychotic clozapine, linking BACE1-NRG1/ErbB4 signaling to synaptic function and psychiatric phenotypes. BACE1 knockout mice, behavioral assays, co-immunoprecipitation (ErbB4-PSD95), dendritic spine quantification, pharmacological rescue with clozapine PNAS High 18385378
2012 GSK3β specifically (not GSK3α) regulates BACE1 gene transcription and expression via NF-κB signaling; specific inhibition of GSK3β reduces BACE1-mediated APP cleavage and Aβ production, decreases amyloid deposition, and rescues memory deficits in double-transgenic AD mice. Isoform-specific inhibition, NF-κB reporter assays, BACE1 transcription assays, transgenic AD mouse model, behavioral testing The Journal of clinical investigation Medium 23202730
2012 BACE1 is a major neuronal sheddase; proteome-wide SPECS method identified 34 novel BACE1 substrates in primary neurons including seizure-protein 6, L1, CHL1, and contactin-2, validated in BACE1 inhibitor-treated and BACE1 knockout mouse brains, pointing to roles in neurite outgrowth and synapse formation. Metabolic glycan labeling, click chemistry-mediated biotinylation (SPECS), mass spectrometry, validation in BACE1 KO and inhibitor-treated mouse brains The EMBO journal High 22728825
2011 Sphingosine-1-phosphate (S1P) directly binds full-length BACE1 and increases its proteolytic activity; inhibition of sphingosine kinase (SphK) or knockdown of SphK or overexpression of S1P-degrading enzymes decreases BACE1 activity and Aβ production in mouse neurons. Direct binding assay (S1P to BACE1), SphK inhibitor treatment, RNAi knockdown, overexpression of S1P-degrading enzymes, BACE1 activity assays The Journal of neuroscience Medium 21543615
2011 BACE1 and ADAM10 cleave type I and III neuregulin-1 (Nrg1) at two adjacent sites (BACE1 site 8 amino acids downstream of ADAM10 site); both generate signaling-capable N-terminal fragments activating ErbB receptors (phosphorylated Akt and ERK), but specific inhibition of BACE1 (not ADAM10) impairs myelination in co-culture, indicating BACE1 cleavage of Nrg1 is specifically required for myelination. Cleavage site mapping, optimized electrophoresis, ErbB receptor phosphorylation assays, BACE1/ADAM10 inhibitor treatment, co-culture myelination assay The Journal of biological chemistry High 21576249
2013 BACE1 directly cleaves membrane-anchored Jagged1 (Jag1), reducing Jag1 shedding; in BACE1-null mice, reduced Jag1 shedding enhances Notch signaling via cell-cell juxtacrine interactions, leading to increased astrogenesis and decreased neurogenesis in the hippocampus during early development. BACE1 knockout mice, overexpression of BACE1, biochemical cleavage assays, cell counting (neurogenesis/astrogenesis), Notch signaling assays Cell reports High 23831026
2013 APP and BACE-1 are largely segregated in distinct vesicles under physiological conditions in neurons (BACE-1 in acidic recycling endosomes; APP in Golgi-derived vesicles); neuronal activity triggers APP routing into BACE-1-positive recycling endosomes via a clathrin-dependent endocytic mechanism, enabling their convergence and amyloidogenic processing. Live imaging of dendritic APP/BACE-1-containing vesicles in hippocampal neurons, clathrin inhibition, subcellular fractionation, activity induction paradigms Neuron High 23931995
2015 APP and BACE-1 interact in both biosynthetic and endocytic compartments, particularly at recycling microdomains such as dendritic spines and presynaptic boutons; in axons, APP and BACE-1 are co-transported and interact during transit; the Alzheimer's disease-protective Icelandic mutation greatly attenuates APP-BACE-1 interaction. Fluorescence complementation optical assay for APP-BACE-1 interaction, endosomal fate-tracking assays in hippocampal neurons, Icelandic mutant APP analysis Nature neuroscience High 26642089
2016 USP8, an endosome-associated deubiquitinating enzyme, deubiquitinates BACE1 at lysine 501, maintaining BACE1 in recycling endosomes; RNAi depletion of USP8 increases BACE1 ubiquitination, promotes BACE1 accumulation in early and late endosomes/lysosomes, reduces BACE1 levels, and decreases BACE1-mediated APP cleavage and Aβ generation. RNAi knockdown of USP8, ubiquitination assays, endosomal co-localization, western blotting, Aβ/sAPPβ measurement in H4 neuroglioma cells The Journal of biological chemistry Medium 27302062
2012 SUMO1 interacts with the dileucine motif of BACE1 and regulates BACE1 protein levels; altering SUMO1 (but not SUMO2 or SUMO3 alone) modulates BACE1 protein levels and consequently APP processing and Aβ generation; BACE1 levels increase in response to Aβ or apoptosis in a SUMO1-dependent manner. Co-immunoprecipitation, gain/loss of function experiments, western blotting, Aβ measurement, APP transgenic mice Neurobiology of aging Medium 22975420
2016 Autophagy-lysosomal pathway regulates BACE1 trafficking and degradation; induction of neuronal autophagy enhances BACE1 turnover suppressible by lysosomal inhibition; BACE1 co-migrates with autophagic vacuoles along axons in a retrograde manner; in mutant APP transgenic neurons, autophagic vacuole-associated BACE1 accumulates in distal axons enhancing β-cleavage, and Snapin-enhanced retrograde transport restores BACE1 delivery to lysosomes. Live imaging of axonal transport, autophagy induction/inhibition, lysosomal inhibition, Snapin overexpression, mutant APP transgenic neurons and mice The Journal of biological chemistry Medium 28028177
2015 BACE1 is highly enriched in synaptic vesicles isolated from rat brain; BACE1 localizes in close proximity to synaptic vesicle marker synaptophysin in intact hippocampal neurons as shown by proximity ligation assay, supporting BACE1-mediated APP processing at the synapse. Controlled-pore glass chromatography synaptic vesicle isolation, western blotting, proximity ligation assay in primary hippocampal neurons Journal of neurochemistry Medium 26296617
2014 Reticulon 3 (RTN3) interacts with BACE1 and negatively regulates its activity; RTN3-null mice show increased BACE1 protein levels, enhanced APP processing at the β-secretase site, and accelerated amyloid deposition in Alzheimer's mouse models. RTN3 knockout mice, western blotting, APP processing biochemical assays, amyloid plaque quantification in AD mouse models The Journal of neuroscience Medium 25319692
2014 BACE1 cleaves human contactin-2 at a site near its GPI membrane linker domain; BACE1 overexpression increases soluble contactin-2 in conditioned media, pharmacological BACE1 inhibition decreases it, and mutation of the BACE1 cleavage site (1008MM/AA) dramatically impairs contactin-2 shedding; BACE1 activity tightly regulates contactin-2 cell surface levels in CHO cells and primary neurons. BACE1 overexpression, pharmacological inhibition, cleavage site mutagenesis, immunofluorescence, surface biotinylation assays, conditioned media ELISA Molecular neurodegeneration High 24405708
2012 Oxidative stress increases BACE1 protein levels via the PKR-eIF2α pathway; specific inhibition of PKR-eIF2α signaling attenuates BACE1 protein levels under H2O2-induced oxidative stress in human neuroblastoma cells, and activated PKR, phospho-eIF2α, and BACE1 are co-elevated in AD cortices and APP/PS1 mice. Western blotting, PKR/eIF2α inhibitors, H2O2 treatment, human AD brain samples, APP/PS1 knock-in mice Biochimica et biophysica acta Medium 22306812
2011 NO differentially modulates BACE1: low concentrations (<100 nM NO) suppress BACE1 transcription via NO/cGMP-PKG signaling (likely through PGC-1α activation), while higher NO levels (0.1-100 μM) induce S-nitrosylation of BACE1 at cysteine residues, inactivating the enzyme without altering expression; H2O2 upregulates BACE1 expression via transcriptional activation. BACE1 activity assays, transcription assays, S-nitrosylation biochemistry, signaling pathway inhibitors (PKG inhibitor), cultured neurons Molecular neurodegeneration Medium 21371311
2017 BACE1 regulates retrograde trafficking from endosomes to the TGN via Par3/aPKC-mediated phosphorylation of BACE1 at Ser498, which promotes BACE1-PACS1 interaction; in human AD brains, Ser498 phosphorylation of BACE1 is significantly decreased, suggesting defective retrograde transport contributes to BACE1 endosomal accumulation. Par3/aPKC overexpression and knockdown, BACE1 Ser498 phospho-specific analysis, co-immunoprecipitation (BACE1-PACS1), endosomal trafficking assays, human AD brain western blotting Neurobiology of aging Medium 28946017
2012 Sorting nexin 12 (SNX12) interacts with BACE1 in early endosomes and regulates BACE1 endocytosis; SNX12 overexpression reduces Aβ, sAPPβ, and APP β-CTF without altering γ-secretase activity or in vitro BACE1 activity, while SNX12 downregulation increases BACE1 endocytosis and reduces cell surface BACE1. Co-immunoprecipitation (SNX12-BACE1), overexpression/knockdown, APP processing biochemical assays, endocytosis assays, human AD brain western blotting Molecular neurodegeneration Medium 22709416
2006 BACE1 in human brain tissue occurs as a dimer, whereas the soluble ectodomain of truncated BACE1 occurs exclusively in monomeric form; mutational analysis of active sites suggests BACE1 may acquire specific catalytic activity upon oligomerization stabilized by transmembrane and cytoplasmic domains. Analysis of BACE1 in human brain tissue, truncation and active-site mutagenesis, biochemical dimerization analysis Neuro-degenerative diseases Low 17047367
2015 BACE1 in axons and Schwann cells is equally required for optimal remyelination of injured sciatic nerves; nerve injury induces BACE1 transcription and elevated BACE1 protein in Schwann cells, where type I (not type III) Nrg1 is induced, and abolished Nrg1 cleavage in BACE1-null Schwann cells contributes to impaired remyelination. Sciatic nerve segment transplantation (swapping between BACE1-null and wild-type), nerve injury models, western blotting, immunohistochemistry, BACE1 transcript quantification The Journal of neuroscience High 25740511
2020 AP-2 (protein complex-2 endocytic adaptor) prevents amyloidogenesis by regulating BACE1 endosomal trafficking and delivery to lysosomes downstream of BACE1 endocytosis; conditional AP-2 knockout mice show increased Aβ production due to BACE1 accumulation in late endosomes/autophagosomes, and deletion of BACE1 in AP-2 KO neurons decreases amyloidogenesis and mitigates synapse loss. Conditional AP-2 KO mice, iPSC-derived AD patient neurons, western blotting, endosomal localization, Aβ measurement, genetic rescue (BACE1 deletion in AP-2 KO neurons) EMBO reports High 32323475
2021 BACE1 is required for optimal synaptic vesicle release; BACE1 deficiency or inhibition decreases synaptic vesicle docking in active zones, reduces hippocampal LTP, and impairs learning; levels of mGluR1 are reduced in BACE1-null mice, and mGluR1 positive allosteric modulators rescue LTP and cognitive deficits caused by BACE1 deficiency or inhibition. BACE1 knockout mice, BACE1 inhibitors (Verubecestat, Lanabecestat), electrophysiology (LTP), electron microscopy (vesicle docking), behavioral testing, mGluR1 PAM pharmacological rescue Molecular psychiatry High 34158621
2022 Microglial BACE1 deficiency enhances Aβ clearance (not by reducing APP processing) by increasing a phagocytic microglial gene signature and enhancing autophagolysosome function; BACE1 deletion in microglia activates PI3K-mTOR-HIF-1α signaling (mTOR phosphorylated at Ser2448) and abolishes cleavage of IL-1R2 and Toll-like receptors, contributing to enhanced phagocytic signaling via PI3K and p38 MAPK. Microglial-specific Bace1 deletion in 5xFAD mice, scRNA-seq, amyloid plaque quantification, LTP measurement, in vitro BACE1 silencing/inhibition in microglia-derived cells, phagocytosis assays Science advances High 35857844
2022 BACE1 deficiency in microglia facilitates their transition from homeostatic to stage 1 disease-associated microglia (DAM-1) by elevating transcription factors (Jun, Jund, Btg2, Erg1, Junb, Fos, Fosb); abolished cleavage of IL-1R2 and Toll-like receptors by BACE1 inhibition contributes to enhanced PI3K and p38 MAPK signaling. Targeted Bace1 deletion in adult 5xFAD microglia, scRNA-seq of purified microglia, BACE1 pharmacological inhibition in microglia-derived cells, amyloid plaque quantification Science advances High 35714196
2023 BACE1 in astrocytes cleaves insulin receptors (IR) on the astrocyte surface; BACE1 deficiency abolishes IR cleavage, enhancing insulin receptor pathway signaling and upregulating Clusterin (CLU) and Cxcl14 expression; elevated astrocytic CLU enhances Aβ uptake and degradation, and astrocyte-specific BACE1 knockout in 5xFAD mice significantly reduces cortical amyloid plaque load. Astrocyte-specific Bace1 KO (Bace1fl/fl;Gfap-cre), scRNA-seq of purified astrocytes, siRNA knockdown, western blotting, Aβ uptake/degradation assays, amyloid plaque quantification Molecular neurodegeneration High 37143090
2015 sAPPα (the product of α-secretase cleavage of AβPP) is a potent endogenous direct inhibitor of BACE1, likely by an allosteric mechanism; sAPPβ (differing only by a 16-amino acid C-terminal truncation) adopts a structurally distinct conformation by small-angle X-ray scattering and does not inhibit BACE1. In vitro BACE1 inhibition assay with recombinant sAPPα, small-angle X-ray scattering (structural comparison of sAPPα vs sAPPβ) Journal of Alzheimer's disease Medium 26401691
2009 Mutant presenilin 1 (PS1) increases BACE1 expression and activity; this upregulation requires gamma-secretase cleavage of APP and is proportional to secreted Aβ42 (not AICD), identifying Aβ42 as the APP derivative that mediates PS1 mutation-induced BACE1 overexpression. Transient and stable transfection with PS1 mutants, gamma-secretase inhibition, western blotting, BACE1 activity assays, PS1 mutant knock-in mice, human FAD brain tissue The Journal of biological chemistry Medium 19196715
2017 p75 neurotrophin receptor interacts with BACE1, and this interaction is enhanced by Aβ; p75 promotes BACE1 and APP co-localization in early endosomes via JNK-mediated phosphorylation of APP-Thr668 and BACE1-Ser498, enhancing amyloidogenesis in cortical neurons. Co-immunoprecipitation (p75-BACE1), immunofluorescence co-localization, early endosome fractionation, JNK inhibition, cortical neuron cultures Journal of neurochemistry Low 28869759
2007 Receptor tyrosine kinase (RTK) stimulation (EGF, NGF receptors) enhances BACE activity and Aβ production by promoting BACE1 internalization into endosomes and Golgi; this enhancement requires Src family kinase activity and endosomal internalization (Rab5-dependent), and is abolished by dominant-negative Rab5 or Src inhibitors. RTK stimulation (EGF, NGF), Src inhibitors, Src RNAi, dominant-negative Rab5, BACE1 activity assays, Aβ measurement, mouse hippocampus experiments Cell research Medium 17325690
2021 Rab35 negatively regulates Aβ production by sorting APP and BACE1 out of the endosomal network via distinct effectors: OCRL mediates BACE1 trafficking and ACAP2 mediates APP trafficking; Rab35 overexpression prevents amyloidogenic trafficking of APP and BACE1 induced by high glucocorticoid levels. Rab35 overexpression/knockdown, effector (OCRL, ACAP2) studies, APP/BACE1 endosomal trafficking assays, Aβ measurement, glucocorticoid treatment Cell death & disease Medium 34876559
2011 Aβ42 activates BACE1 gene transcription through the JNK/c-jun signaling pathway, creating a positive feedback loop; Aβ40 has much less effect on BACE1 expression. Aβ42/Aβ40 treatment of neuronal cells, BACE1 transcription assays, JNK pathway inhibition Journal of Alzheimer's disease Medium 21897006
2019 MMP13 regulates BACE1 protein levels post-transcriptionally through PI3K signaling and eIF4B-mediated translational control; eIF4B phosphorylation at Ser422 mediates MMP13's effect on BACE1, and deletion of the BACE1 5'UTR abolishes MMP13-mediated regulation; MMP13 inhibition reduces BACE1 levels and Aβ deposition in APP/PS1 AD mice. High-throughput BACE1 promoter/5'UTR luciferase screen, eIF4B mutagenesis (S422R), 5'UTR deletion, PI3K inhibition, APP/PS1 mouse hippocampal Mmp13 knockdown, Aβ quantification Brain Medium 30596903

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Bace1 modulates myelination in the central and peripheral nervous system. Nature neuroscience 482 17099708
2012 Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. The Journal of clinical investigation 379 23202730
2005 Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. The Journal of biological chemistry 297 15987683
2007 Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron 292 17553422
2012 Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. The EMBO journal 274 22728825
2001 Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Current biology : CB 259 11525745
2007 BACE1 regulates voltage-gated sodium channels and neuronal activity. Nature cell biology 255 17576410
2008 Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice. Proceedings of the National Academy of Sciences of the United States of America 234 18385378
2013 Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 190 23931995
2002 Beta-secretase (BACE) as a drug target for Alzheimer's disease. Advanced drug delivery reviews 173 12453676
2004 Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 166 15059975
2011 BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. The Journal of neuroscience : the official journal of the Society for Neuroscience 155 21543615
2001 The beta-secretase, BACE: a prime drug target for Alzheimer's disease. Journal of molecular neuroscience : MN 154 11816789
2018 The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease. EMBO molecular medicine 147 30224383
2012 Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochimica et biophysica acta 147 22306812
2015 Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nature neuroscience 145 26642089
2005 BACE is degraded via the lysosomal pathway. The Journal of biological chemistry 144 16033761
2004 Degradation of BACE by the ubiquitin-proteasome pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 135 15289451
2003 BACE1 suppression by RNA interference in primary cortical neurons. The Journal of biological chemistry 130 14600149
2005 Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 118 15857888
2017 BACE inhibition-dependent repair of Alzheimer's pathophysiology. Proceedings of the National Academy of Sciences of the United States of America 110 28739891
2014 Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biological psychiatry 108 25599931
2011 Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination. The Journal of biological chemistry 101 21576249
2019 BACE-1 and γ-Secretase as Therapeutic Targets for Alzheimer's Disease. Pharmaceuticals (Basel, Switzerland) 98 30893882
2011 Amyloid-β production: major link between oxidative stress and BACE1. Neurotoxicity research 98 22002808
2019 Investigational BACE inhibitors for the treatment of Alzheimer's disease. Expert opinion on investigational drugs 97 31661331
2017 BACE-1 Inhibitors: From Recent Single-Target Molecules to Multitarget Compounds for Alzheimer's Disease. Journal of medicinal chemistry 97 28749667
2016 Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors. Journal of medicinal chemistry 94 26696252
2017 Role of BACE1 in Alzheimer's synaptic function. Translational neurodegeneration 93 28855981
2011 Differential regulation of BACE1 expression by oxidative and nitrosative signals. Molecular neurodegeneration 93 21371311
2002 A non-amyloidogenic function of BACE-2 in the secretory pathway. Journal of neurochemistry 93 12065613
2016 miR-186 is decreased in aged brain and suppresses BACE1 expression. Journal of neurochemistry 91 26710318
2012 BACE1 in Alzheimer's disease. Clinica chimica acta; international journal of clinical chemistry 76 22926063
2001 Ligand binding and physico-chemical properties of ASP2, a recombinant odorant-binding protein from honeybee (Apis mellifera L.). European journal of biochemistry 72 11168415
2022 BACE1: More than just a β-secretase. Obesity reviews : an official journal of the International Association for the Study of Obesity 70 35119166
2009 Function, regulation and therapeutic properties of beta-secretase (BACE1). Seminars in cell & developmental biology 70 19429494
2013 BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell reports 66 23831026
2019 BACE1-AS prevents BACE1 mRNA degradation through the sequestration of BACE1-targeting miRNAs. Journal of chemical neuroanatomy 65 30959172
2015 ADAM10 and BACE1 are localized to synaptic vesicles. Journal of neurochemistry 64 26296617
2012 BACE1 dependent neuregulin processing: review. Current Alzheimer research 64 22455478
2022 Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Science advances 62 35857844
2014 Icariin decreases the expression of APP and BACE-1 and reduces the β-amyloid burden in an APP transgenic mouse model of Alzheimer's disease. International journal of biological sciences 62 24550686
2019 New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorganic & medicinal chemistry letters 61 30709653
2016 The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation. The Journal of biological chemistry 61 27302062
2009 Cell biology, regulation and inhibition of beta-secretase (BACE-1). The FEBS journal 61 19292866
2016 Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Scientific reports 60 26912421
2016 Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation. The Journal of biological chemistry 60 28028177
2017 The physical approximation of APP and BACE-1: A key event in alzheimer's disease pathogenesis. Developmental neurobiology 59 29106038
2011 Amyloid-β₄₂ activates the expression of BACE1 through the JNK pathway. Journal of Alzheimer's disease : JAD 54 21897006
2016 Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia 53 27138913
2014 Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. The Journal of neuroscience : the official journal of the Society for Neuroscience 53 25319692
2009 Cholinesterase and BACE1 inhibitory diterpenoids from Aralia cordata. Archives of pharmacal research 52 19898803
2022 BACE-1 inhibition facilitates the transition from homeostatic microglia to DAM-1. Science advances 51 35714196
2012 SUMO1 modulates Aβ generation via BACE1 accumulation. Neurobiology of aging 51 22975420
2010 BACE: Therapeutic target and potential biomarker for Alzheimer's disease. The international journal of biochemistry & cell biology 51 20817005
2008 Impact of cholesterol level upon APP and BACE proximity and APP cleavage. Biochemical and biophysical research communications 51 18374657
2003 Cloning and expression of the rat BACE1 promoter. Journal of neuroscience research 48 12815710
2019 MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. Brain : a journal of neurology 47 30596903
2020 AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons. EMBO reports 46 32323475
2009 Mutant presenilin 1 increases the expression and activity of BACE1. The Journal of biological chemistry 46 19196715
2006 Human beta-secretase (BACE) and BACE inhibitors: progress report. Current topics in medicinal chemistry 46 16712492
2015 sAβPPα is a Potent Endogenous Inhibitor of BACE1. Journal of Alzheimer's disease : JAD 45 26401691
2012 Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Molecular neurodegeneration 45 22709416
2011 BACE1 as a potential biomarker for Alzheimer's disease. Journal of Alzheimer's disease : JAD 45 21403391
2019 The effect of BACE1-AS on β-amyloid generation by regulating BACE1 mRNA expression. BMC molecular biology 44 31570097
2018 Consequences of Pharmacological BACE Inhibition on Synaptic Structure and Function. Biological psychiatry 43 29945719
2014 BACE1 activity regulates cell surface contactin-2 levels. Molecular neurodegeneration 43 24405708
2014 BACE1 and cholinesterase inhibitory activities of Nelumbo nucifera embryos. Archives of pharmacal research 41 25300425
2005 Biochemical and cell-based assays for characterization of BACE-1 inhibitors. Analytical biochemistry 41 15958191
2007 Receptor tyrosine kinases positively regulate BACE activity and Amyloid-beta production through enhancing BACE internalization. Cell research 39 17325690
2003 BACE-2 is overexpressed in Down's syndrome. Experimental neurology 39 12895444
2010 IGF-1 reduces BACE-1 expression in PC12 cells via activation of PI3-K/Akt and MAPK/ERK1/2 signaling pathways. Neurochemical research 38 20821260
2003 BACE1 and BACE2 in pathologic and normal human muscle. Experimental neurology 37 12618121
2018 BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP-Dependent Mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 29632166
2012 Lysophosphatidic acid induces increased BACE1 expression and Aβ formation. Biochimica et biophysica acta 36 23036978
2023 BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides. Molecular neurodegeneration 34 37143090
2021 Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease. European journal of medicinal chemistry 34 33862517
2021 BACE1 controls synaptic function through modulating release of synaptic vesicles. Molecular psychiatry 34 34158621
2016 Future Therapeutics in Alzheimer's Disease: Development Status of BACE Inhibitors. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy 33 27023706
2015 Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 25740511
2017 Polymethoxyflavones: Novel β-Secretase (BACE1) Inhibitors from Citrus Peels. Nutrients 31 28869548
2009 BACE and gamma-secretase characterization and their sorting as therapeutic targets to reduce amyloidogenesis. Neurochemical research 31 19760173
2014 Occludin deficiency with BACE1 elevation in cerebral amyloid angiopathy. Neurology 30 24739782
2022 Guanidine-based β amyloid precursor protein cleavage enzyme 1 (BACE-1) inhibitors for the Alzheimer's disease (AD): A review. Bioorganic & medicinal chemistry 29 36265268
2017 BACE1 Dynamics Upon Inhibition with a BACE Inhibitor and Correlation to Downstream Alzheimer's Disease Markers in Elderly Healthy Participants. Journal of Alzheimer's disease : JAD 27 28157093
2017 p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. Journal of neurochemistry 26 28869759
2012 The accessory Sec protein Asp2 modulates GlcNAc deposition onto the serine-rich repeat glycoprotein GspB. Journal of bacteriology 26 22885294
2019 The β-secretase (BACE) inhibitor NB-360 in preclinical models: From amyloid-β reduction to downstream disease-relevant effects. British journal of pharmacology 25 30657591
2017 Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1. Neurobiology of aging 25 28946017
2019 Multiple BACE1 inhibitors abnormally increase the BACE1 protein level in neurons by prolonging its half-life. Alzheimer's & dementia : the journal of the Alzheimer's Association 24 31416794
2021 Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production. Cell death & disease 23 34876559
2011 Asp2 and Asp3 interact directly with GspB, the export substrate of the Streptococcus gordonii accessory Sec System. Journal of bacteriology 23 21531800
2019 Semi-synthetic isoflavones as BACE-1 inhibitors against Alzheimer's disease. Bioorganic chemistry 22 30927588
2016 β-Secretase (BACE1) inhibitory and neuroprotective effects of p-terphenyls from Polyozellus multiplex. Food & function 22 27511641
2008 Mutational analysis of the conserved Asp2.50 and ERY motif reveals signaling bias of the urotensin II receptor. Molecular pharmacology 22 18509066
2000 The amino terminus of PKA catalytic subunit--a site for introduction of posttranslational heterogeneities by deamidation: D-Asp2 and D-isoAsp2 containing isozymes. Protein science : a publication of the Protein Society 22 11152138
2022 Dual Inhibitors of AChE and BACE-1 for Reducing Aβ in Alzheimer's Disease: From In Silico to In Vivo. International journal of molecular sciences 21 36361906
2006 Amyloid precursor protein and BACE function as oligomers. Neuro-degenerative diseases 21 17047367
2022 Unmasking BACE1 in aging and age-related diseases. Trends in molecular medicine 20 36509631
2014 Can BACE1 inhibition mitigate early axonal pathology in neurological diseases? Journal of Alzheimer's disease : JAD 20 24081378

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