Affinage

BACE1

Beta-secretase 1 · UniProt P56817

Length
501 aa
Mass
55.8 kDa
Annotated
2026-04-28
100 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BACE1 is a transmembrane aspartyl protease that serves as the principal neuronal β-secretase, catalyzing the rate-limiting cleavage of APP to initiate amyloid-β (Aβ) production while also functioning as a broad sheddase for dozens of type I transmembrane substrates including neuregulin-1 (NRG1), Jagged1, sodium channel β2-subunit, contactin-2, and insulin receptors, thereby regulating myelination, neurogenesis, sodium channel surface expression, and astrocytic Aβ clearance (PMID:15987683, PMID:20041192, PMID:22728825, PMID:18385378, PMID:23831026, PMID:17576410, PMID:37143090). BACE1 is regulated at the transcriptional level by NF-κB signaling (activated by Aβ42, GSK3β, and oxidative stress), at the translational level through inhibitory upstream ATGs in its 5′UTR modulated by eIF2α phosphorylation via PKR, and post-translationally by K501 ubiquitination directing GGA3-dependent lysosomal degradation, S-nitrosylation-mediated inactivation, and direct activation by sphingosine-1-phosphate (PMID:18263584, PMID:23202730, PMID:15034149, PMID:22306812, PMID:20484053, PMID:21371311, PMID:21543615). Subcellular trafficking through endosomal compartments—governed by JNK-mediated phosphorylation of S498, GGA1/retromer-dependent sorting from early to recycling endosomes, AP-2-directed lysosomal delivery, and activity-dependent convergence with APP in acidic recycling endosomes—is a critical determinant of amyloidogenic cleavage (PMID:29142073, PMID:32323475, PMID:23931995, PMID:26642089). Beyond APP processing, BACE1 directly interacts with adenylate cyclase via its transmembrane domain to suppress cAMP/PKA/CREB signaling independently of Aβ generation (PMID:22895721).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2001 High

    The question of where BACE1 encounters APP was addressed by showing that BACE1 localizes to cholesterol-dependent lipid rafts containing APP, establishing that membrane microdomains provide a platform for amyloidogenic processing.

    Evidence Detergent and non-detergent lipid raft fractionation, immunoisolation, and cholesterol depletion across three cell lines

    PMID:11525745

    Open questions at the time
    • Whether raft association is essential for cleavage in vivo was not tested
    • The mechanism of cholesterol-dependent BACE1 raft targeting was not defined
  2. 2002 High

    The mechanism linking oxidative stress to BACE1 upregulation was established: lipid peroxidation products (HNE) increase BACE1 protein and activity, positioning oxidative damage as a driver of amyloidogenesis.

    Evidence Pro-oxidant treatment of NT2 neurons with western blot for BACE1 and APP C-terminal fragments; α-tocopherol rescue

    PMID:12270690

    Open questions at the time
    • Whether the effect is transcriptional or post-translational was not resolved at this stage
  3. 2004 High

    Two degradation routes and a translational control mechanism for BACE1 were defined: proteasomal degradation via ubiquitination, lysosomal degradation requiring the C-terminal di-leucine motif, and translational repression by upstream ATGs in the 5′UTR, establishing that BACE1 levels are controlled at multiple post-transcriptional checkpoints.

    Evidence Proteasome inhibitor (lactacystin) stabilization and ubiquitination assays; lysosomal inhibitor accumulation with di-leucine mutagenesis in primary neurons; BACE1 5′UTR reporter/mutagenesis assays

    PMID:15034149 PMID:15289451 PMID:16033761

    Open questions at the time
    • The specific ubiquitin linkage types and the lysine residue were not yet mapped
    • How upstream ATG skipping is regulated in disease was unclear
  4. 2005 High

    Genetic knockout definitively established BACE1 as the rate-limiting neuronal β-secretase and revealed a non-APP function: BACE1-null mice show nearly abolished neuronal Aβ and altered voltage-gated sodium channel properties.

    Evidence BACE1-knockout, BACE2-knockout, and double-knockout mice with Aβ measurement and sodium channel electrophysiology

    PMID:15987683

    Open questions at the time
    • The sodium channel substrate was not identified at this stage
    • Glial β-secretase activity source was not identified
  5. 2006 High

    Heparin was shown to activate BACE1 via binding to its pro-domain, increasing Vmax and promoting autocatalytic processing, revealing a pro-domain-dependent allosteric activation mechanism.

    Evidence In vitro kinetic analysis of recombinant zymogen vs. mature BACE1 with heparin

    PMID:16716081

    Open questions at the time
    • The physiological heparan sulfate proteoglycan ligand in vivo was not identified
    • Whether pro-domain cleavage is rate-limiting in cells was not tested
  6. 2007 High

    Two key non-APP substrates and a trafficking adaptor were identified: BACE1 cleaves the sodium channel β2-subunit to regulate Nav1.1 surface expression, and GGA3 was established as a critical regulator of BACE1 protein levels whose caspase-mediated depletion during ischemia elevates BACE1 and Aβ.

    Evidence BACE1-transgenic mouse electrophysiology and Nav surface analysis; GGA3 RNAi, caspase activation in ischemia models, AD brain validation

    PMID:17553422 PMID:17576410

    Open questions at the time
    • Whether β2 cleavage contributes to AD-related sodium channel dysfunction was not tested
    • The complete GGA3 ubiquitin-recognition mechanism for BACE1 was not yet mapped
  7. 2008 High

    A positive transcriptional feedback loop was defined: Aβ42 activates BACE1 transcription via NF-κB, and BACE1-dependent NRG1 cleavage was established as essential for myelination and synaptic function through ErbB4 signaling.

    Evidence BACE1 promoter-reporter assays with NF-κB mutagenesis and IKK inhibitor; BACE1-KO mouse behavioral/biochemical phenotyping for NRG1/ErbB4/PSD-95

    PMID:18263584 PMID:18385378

    Open questions at the time
    • Whether NF-κB-driven BACE1 upregulation occurs in human AD neurons in vivo was not directly shown
    • The schizophrenia-like phenotype awaits replication in independent BACE1-KO lines
  8. 2009 High

    Unbiased proteomics revealed BACE1 as a broad sheddase of ~68 type I transmembrane proteins with no strict sequence motif, fundamentally expanding its functional scope beyond APP.

    Evidence SILAC quantitative proteomics of conditioned media from BACE1-expressing HEK cells with biochemical validation

    PMID:20041192

    Open questions at the time
    • Neuronal substrate repertoire was not addressed in this epithelial cell system
    • Physiological relevance of most identified substrates was not validated
  9. 2010 High

    The molecular basis of ubiquitin-dependent BACE1 degradation was mapped: K501 monoubiquitination and K63-linked polyubiquitination enable GGA3 recognition via its VHS domain, resolving how GGA3 controls BACE1 turnover.

    Evidence BACE1 K501 mutagenesis, GGA3 VHS domain (N91A) and DXXLL (L276A) mutants, rescue in GGA3-depleted cells

    PMID:20484053

    Open questions at the time
    • The E3 ubiquitin ligase responsible for K501 ubiquitination was not identified
    • Whether K63-linked chains serve as degradation or trafficking signals was not fully resolved
  10. 2011 High

    Multiple new regulatory inputs were defined: S1P directly binds and activates BACE1, NO inactivates BACE1 via S-nitrosylation, and BACE1-specific NRG1 cleavage sites were mapped showing functional distinction from ADAM10 cleavage in myelination.

    Evidence S1P-BACE1 binding assay with SphK inhibitors/RNAi; NO donor dose-response with S-nitrosylation detection and AD brain analysis; BACE1/ADAM10 cleavage site mapping with myelination co-culture assay

    PMID:21371311 PMID:21543615 PMID:21576249

    Open questions at the time
    • The S1P binding site on BACE1 was not mapped
    • Whether S-nitrosylation loss in AD is cause or consequence was not determined
  11. 2012 High

    A systems-level picture of BACE1 regulation emerged: GSK3β drives BACE1 transcription via NF-κB; oxidative stress increases BACE1 translation via PKR-eIF2α; BACE1 suppresses cAMP/PKA/CREB via transmembrane interaction with adenylate cyclase; GGA1 was identified as a synergistic regulator with GGA3; and neuron-specific proteomics identified 34 novel nervous system substrates including seizure-protein 6 and contactin-2.

    Evidence GSK3β-specific inhibitors and NF-κB reporter in AD mice; PKR-eIF2α inhibitors with AD brain correlation; BACE1 transmembrane domain mutant Co-IP with adenylate cyclase in Aβ-free transgenic mice; GGA1 siRNA/GGA3-KO with TBI model; SPECS glycoproteomics in primary neurons and BACE1-KO brains

    PMID:22306812 PMID:22728825 PMID:22836275 PMID:22895721 PMID:23202730

    Open questions at the time
    • The adenylate cyclase interaction domain on BACE1 was not structurally resolved
    • Whether the cAMP effect contributes to AD pathology was not tested in disease models
    • The E3 ligase for BACE1 K501 remained unidentified
  12. 2013 High

    Subcellular segregation of APP and BACE1 was shown to be activity-dependent: in resting hippocampal neurons APP and BACE1 reside in separate vesicle populations, but neuronal activity routes APP into BACE1-positive acidic recycling endosomes via clathrin-dependent endocytosis; separately, BACE1 cleavage of Jagged1 was shown to regulate Notch-dependent neurogenesis/astrogenesis balance.

    Evidence Live dendritic vesicle imaging with clathrin inhibition in hippocampal neurons and AD brain comparison; BACE1-KO mouse hippocampal BrdU/cell-fate analysis with Jagged1 cleavage assays

    PMID:23831026 PMID:23931995

    Open questions at the time
    • The signal transduction pathway from neuronal activity to APP re-routing was not fully defined
    • Whether Jagged1 cleavage contributes to adult neurogenesis deficits in AD was not tested
  13. 2014 High

    BACE1 was shown to cleave contactin-2 near its GPI anchor, tightly controlling its surface levels, and RTN3 was established as a negative regulator of BACE1 whose loss enhances amyloid deposition.

    Evidence Contactin-2 cleavage site mutagenesis (MM/AA) with surface biotinylation; RTN3-KO mice crossed with AD models

    PMID:24405708 PMID:25319692

    Open questions at the time
    • Functional consequences of contactin-2 shedding on axonal adhesion in vivo were not assessed
    • The mechanism by which RTN3 inhibits BACE1 (sequestration vs. degradation) was not resolved
  14. 2015 High

    APP-BACE1 proximity in biosynthetic and endocytic compartments was directly visualized; the Icelandic protective APP mutation greatly attenuated this interaction; separately, BACE1 was shown to be required in both axons and Schwann cells for remyelination via NRG1 type I cleavage, and sAPPα was identified as a potent allosteric BACE1 inhibitor.

    Evidence Fluorescence complementation in hippocampal neurons with Icelandic mutant; nerve segment transplant between BACE1-null and WT mice; in vitro BACE1 inhibition kinetics with SAXS structural analysis of sAPPα vs. sAPPβ

    PMID:25740511 PMID:26401691 PMID:26642089

    Open questions at the time
    • Whether sAPPα reaches sufficient local concentration to inhibit BACE1 in vivo was not demonstrated
    • The sAPPα binding site on BACE1 was not mapped
  15. 2017 High

    The phosphorylation-dependent endosomal sorting mechanism was resolved: JNK phosphorylates BACE1 at S498, enabling GGA1/retromer-mediated exit from early endosomes to recycling endosomes, thereby reducing Aβ production by limiting BACE1 residence time in APP-enriched acidic compartments.

    Evidence BACE1 S498D/S498A phosphomimetic mutants with GGA1/retromer component knockdown and Aβ measurement in primary neurons

    PMID:29142073

    Open questions at the time
    • Whether JNK-mediated BACE1 phosphorylation is dysregulated in AD was not shown
    • Other kinases that may phosphorylate S498 were not excluded
  16. 2019 High

    Translational control of BACE1 was further elaborated: MMP13 inhibition reduces BACE1 via PI3K-eIF4B(S422)-dependent translational repression requiring the 5′UTR, and the antisense lncRNA BACE1-AS stabilizes BACE1 mRNA by sequestering miRNAs.

    Evidence eIF4B S422R mutagenesis with BACE1 5′UTR-reporter and PI3K inhibitor; hippocampal Mmp13 knockdown in AD mice; BACE1-AS overexpression/knockdown with miRNA measurements

    PMID:30596903 PMID:30959172

    Open questions at the time
    • The full set of miRNAs sequestered by BACE1-AS was not defined
    • Whether MMP13's effect on BACE1 is direct or indirect (via extracellular proteolysis) was not resolved
  17. 2020 High

    AP-2 was established as an independent regulator of BACE1 endosomal trafficking: conditional AP-2 knockout causes BACE1 accumulation in late endosomes/autophagosomes and increases Aβ, and AP-2 is reduced in late-onset AD patient iPSC neurons.

    Evidence Conditional AP-2 KO mice, iPSC-derived AD neurons, BACE1 trafficking by immunofluorescence/fractionation, BACE1 deletion rescue

    PMID:32323475

    Open questions at the time
    • Whether AP-2 reduction is a cause or consequence of AD pathology was not determined
    • The AP-2 recognition motif on BACE1 was not mapped
  18. 2022 High

    Cell-type-specific BACE1 functions in glia were uncovered: microglial BACE1 deletion reduces plaques not through altered APP processing but through enhanced phagocytic Aβ clearance via PI3K-mTOR-HIF-1α-mediated metabolic reprogramming, without the synaptic plasticity deficits seen with global BACE1 deletion.

    Evidence Microglial-specific Bace1 conditional KO in 5xFAD mice with scRNA-seq, plaque quantification, LTP electrophysiology, and phagocytosis assays

    PMID:35857844

    Open questions at the time
    • Whether the mTOR-HIF-1α mechanism operates in human microglia was not tested
    • The direct BACE1 substrate in microglia driving this phenotype was not identified
  19. 2023 High

    Astrocytic BACE1 was shown to cleave insulin receptors, and its deletion upregulates Clusterin/Cxcl14 expression to enhance Aβ uptake and degradation, attenuating plaque load—establishing a non-neuronal, clearance-focused BACE1 function.

    Evidence Astrocyte-specific Bace1 conditional KO in 5xFAD mice with scRNA-seq, IR cleavage analysis, CLU siRNA, Aβ clearance assays

    PMID:37143090

    Open questions at the time
    • Whether IR cleavage by BACE1 affects astrocytic insulin signaling beyond Clusterin was not explored
    • The relative contribution of astrocytic vs. microglial BACE1 deletion to plaque reduction was not directly compared

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase targeting BACE1 K501, the structural basis of sAPPα allosteric inhibition and S1P activation, whether trafficking dysregulation (AP-2 loss, GGA depletion) is a cause or consequence of AD, and how cell-type-specific BACE1 inhibition strategies can be translated therapeutically to avoid myelination and synaptic side effects.
  • E3 ligase for K501 ubiquitination unknown
  • Structural basis of sAPPα-BACE1 and S1P-BACE1 interactions unresolved
  • No cell-type-specific therapeutic approach validated in humans

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016787 hydrolase activity 4
Localization
GO:0005768 endosome 5 GO:0005764 lysosome 3 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 3
Pathway
R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 4 R-HSA-112316 Neuronal System 3
Partners
ADAM10AP2APPGGA1GGA3PSEN1RTN3SNX12
Complex memberships
BACE1 homodimer

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 BACE1 (Asp2) localizes to low-buoyant density, noncaveolar lipid rafts in an cholesterol-dependent manner; depletion of raft cholesterol abrogates this association and the raft fraction contains other components of the amyloidogenic pathway including APP. Detergent and non-detergent lipid raft fractionation, immunoisolation of caveolin-containing vesicles, cholesterol depletion experiments in three cell lines Current biology : CB High 11525745
2002 BACE1 protein levels and activity are increased by oxidative stress products (4-hydroxynonenal, HNE) generated by ascorbate/FeSO4 or H2O2/FeSO4 in NT2 neurons, and this is accompanied by increased APP C-terminal fragment production; alpha-tocopherol pretreatment prevents BACE1 induction. Treatment of NT2 neurons with pro-oxidant stimuli, western blot for BACE protein, measurement of APP carboxy-terminal fragments, antioxidant protection assay Neurobiology of disease High 12270690
2004 BACE1 protein is degraded via the ubiquitin-proteasome pathway; proteasome inhibitor lactacystin stabilizes BACE1, BACE1 is ubiquitinated, and proteasome inhibition increases APP C99 production and Aβ generation. Proteasome inhibitor treatment (lactacystin), western blot, ubiquitination assay, Aβ and C99 measurement in stably transfected cells FASEB journal High 15289451
2004 BACE1 translation is negatively regulated by multiple upstream ATGs in its 5' UTR; conditions favoring upstream ATG skipping or alternative splicing that removes upstream ATGs relieve this inhibition and increase BACE1 protein; activated astrocytes show increased BACE1 translation independently of splicing. Reporter assays with BACE1 5'UTR constructs, mutagenesis of upstream ATGs, alternative splicing analysis, cell-type specific translation assays Nucleic acids research High 15034149
2005 BACE1 is degraded via the lysosomal pathway; lysosomal inhibitors cause BACE1 accumulation in LAMP2-positive late endosomal/lysosomal compartments; the C-terminal di-leucine motif (L499/L500) is required for efficient lysosomal targeting of BACE1. Lysosomal inhibitor treatment (chloroquine, NH4Cl), immunofluorescence colocalization with LAMP2, di-leucine motif mutagenesis (BACE-LL/AA), western blot in multiple cell types including primary neurons The Journal of biological chemistry High 16033761
2005 BACE1 deficiency in mice results in almost complete block of Aβ generation in neurons (but not glia), indicating BACE1 is the rate-limiting neuronal β-secretase; BACE1-null mice show altered steady-state inactivation of voltage-gated sodium channels in neurons. Genetic knockout mice (bace1-/-, bace2-/-, double knockout), biochemical Aβ measurement, electrophysiology of voltage-gated sodium channels The Journal of biological chemistry High 15987683
2006 Low concentrations of heparin activate BACE1 by binding to its pro-domain, increasing Vmax and decreasing Km; heparin stimulates autocatalytic cleavage of the protease domain; mature BACE1 (pro sequence removed) cannot be stimulated by heparin, indicating the pro domain is required. In vitro recombinant BACE1 enzyme activity assays with heparin at varying concentrations, heparin affinity chromatography, zymogen vs. mature enzyme comparison Biochemistry High 16716081
2007 GGA3, an adaptor protein involved in BACE trafficking, regulates BACE protein levels and β-secretase activity; caspase activation during cerebral ischemia depletes GGA3, leading to post-translational stabilization of BACE and increased Aβ; RNAi silencing of GGA3 elevates BACE and Aβ levels. RNAi silencing, caspase activation experiments, western blot for GGA3 and BACE in ischemia models and AD brain samples, Aβ measurement Neuron High 17553422
2007 BACE1 cleaves the voltage-gated sodium channel β2-subunit; this cleavage releases the β2 intracellular domain, which increases Nav1.1 α-subunit mRNA and protein; however, 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, sodium current electrophysiology, cell-surface Nav expression analysis, mRNA quantification Nature cell biology High 17576410
2008 BACE1-dependent NRG1 processing is required for normal myelination of central and peripheral axons; BACE1-null mice exhibit schizophrenia-like behavioral phenotypes including deficits in prepulse inhibition and altered ErbB4-PSD95 binding, suggesting BACE1-dependent NRG1/ErbB4 signaling regulates synaptic function. BACE1 knockout mice behavioral analysis (prepulse inhibition, hyperactivity, MK-801 sensitivity), co-immunoprecipitation of ErbB4-PSD95, hippocampal spine density analysis, antipsychotic drug treatment Proceedings of the National Academy of Sciences High 18385378
2008 Aβ42 (but not Aβ40) activates BACE1 promoter transactivation via an NF-κB-dependent pathway; this effect requires overexpressed or Swedish-mutant APP generating excess Aβ; presenilin deficiency lowers BACE1 maturation and promoter activity; AICD does not modulate BACE1 activity. BACE1 promoter-reporter constructs, transfection of wild-type and Swedish APP mutant, exogenous Aβ42 application, IκB kinase inhibitor (BMS345541), presenilin-deficient fibroblasts, NF-κB-response-element deletion mutants The Journal of biological chemistry High 18263584
2008 APP and BACE1 come into close proximity intracellularly (not primarily at the cell surface); cholesterol level alterations affect BACE proximity and APP cleavage, consistent with cholesterol modulating membrane fluidity and intracellular APP/BACE proximity. Time-resolved FRET combined with total internal reflection microscopy (TIRET), sAPP secretion assays with cholesterol manipulation Biochemical and biophysical research communications Medium 18374657
2009 Mutant presenilin 1 (PS1) increases BACE1 expression and activity; this upregulation requires γ-secretase cleavage of APP and is mediated by Aβ42 (not AICD); BACE1 elevation is confirmed in PS1 mutant knock-in mice and FAD cortex. PS1 mutant transfection (transient and stable), PS1 knock-in mice, AD brain tissue analysis, γ-secretase inhibitor treatment, Aβ42 manipulation The Journal of biological chemistry High 19196715
2009 Quantitative proteomics identifies 68 putative BACE1 substrates in human epithelial cells, the vast majority being type I transmembrane proteins; BACE1 functions as a broad sheddase with no consistent cleavage sequence motif. Stable isotope labeling-based quantitative proteomics (SILAC) of conditioned media from BACE1-expressing HEK cells, biochemical validation in cell culture PloS one High 20041192
2010 BACE1 ubiquitination at K501 (primarily monoubiquitination and K63-linked polyubiquitination) is required for GGA3-mediated lysosomal degradation; GGA3 regulates BACE1 levels through ubiquitin-binding (via its VHS domain) rather than exclusively through DXXLL-dileucine motif interaction. Site-directed mutagenesis of BACE1 K501, GGA3 domain mutations (N91A ubiquitin-binding mutant, L276A), co-IP, rescue experiments in GGA3-depleted cells, Aβ measurement The Journal of biological chemistry High 20484053
2011 Sphingosine-1-phosphate (S1P) directly binds full-length BACE1 and increases its proteolytic activity; inhibition of sphingosine kinase (SphK) or knockdown of SphK/overexpression of S1P-degrading enzymes reduces BACE1 activity and Aβ production in mouse neurons. S1P-BACE1 direct binding assay, SphK inhibitors, RNAi knockdown of SphK, S1P-degrading enzyme overexpression, BACE1 activity assays, Aβ measurement in neurons The Journal of neuroscience High 21543615
2011 BACE1 and ADAM10 cleave type I and III NRG1 at two adjacent sites (BACE1 site 8 amino acids downstream of ADAM10 site), releasing a signaling-capable N-terminal fragment that activates ErbB receptors; specific inhibition of BACE1 (but not ADAM10) impairs myelination in co-culture. Cleavage site mapping, BACE1 and ADAM10 specific inhibitors in co-culture myelination assay, ErbB receptor phosphorylation (Akt, ERK readouts), optimized electrophoresis The Journal of biological chemistry High 21576249
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 and Aβ40 treatment of neurons, BACE1 mRNA and protein measurement, JNK pathway inhibition Journal of Alzheimer's disease Medium 21897006
2011 Nitric oxide at low concentrations (<100 nM) suppresses BACE1 transcription via NO/cGMP-PKG/PGC-1α signaling; at higher concentrations (0.1-100 μM), NO causes S-nitrosylation of BACE1 which inactivates the enzyme without altering expression; H2O2 induces BACE1 transcription and activity; BACE1 is highly S-nitrosylated in normal aging brains but reduced in AD. NO donor/H2O2 treatment of neurons, BACE1 activity assays, S-nitrosylation detection, PKG inhibition, PGC-1α pathway analysis, Aβ measurement, brain tissue analysis Molecular neurodegeneration High 21371311
2012 GSK3β (but not GSK3α) regulates BACE1 gene transcription and expression via NF-κB signaling; specific inhibition of GSK3β reduces BACE1-mediated APP cleavage and Aβ production, and reduces amyloid deposition and memory deficits in AD model mice. GSK3β-specific inhibitors, isoform-specific genetic manipulation, BACE1 promoter NF-κB reporter assays, Aβ and plaque measurement, memory tests in double transgenic AD mice The Journal of clinical investigation High 23202730
2012 Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway; specific inhibition of PKR-eIF2α attenuates BACE1 protein levels under oxidative stress; pPKR and peIF2α levels correlate with BACE1 in AD cortices. H2O2-induced oxidative stress in SH-SY5Y cells, PKR/eIF2α pathway inhibitors, immunoblotting for PKR, eIF2α, BACE1 in AD brains and APP/PS1 knock-in mice Biochimica et biophysica acta High 22306812
2012 BACE1 regulates the cAMP/PKA/CREB pathway independently of β-amyloid production; BACE1 interacts with adenylate cyclase via its transmembrane domain, reducing cellular cAMP levels, leading to PKA inactivation and reduced CREB phosphorylation. BACE1 overexpression/downregulation, co-immunoprecipitation with adenylate cyclase, transmembrane domain mutants, cAMP/PKA/CREB activity assays, BACE1 transgenic mice (lacking human Aβ) The Journal of neuroscience High 22895721
2012 BACE1 is a major sheddase in the nervous system, cleaving 34 novel substrates in primary neurons identified by SPECS (secretome protein enrichment with click sugars); validated substrates include seizure-protein 6, L1, CHL1, and contactin-2, pointing to BACE1 roles in neurite outgrowth and synapse formation. SPECS method (metabolic glycan labeling + click chemistry biotinylation), BACE1 inhibitor-treated and BACE1 knockout mouse brains for validation, mass spectrometry The EMBO journal High 22728825
2012 SUMO1 interacts with the dileucine motif of BACE1 and promotes BACE1 protein accumulation; altering SUMO1 levels affects BACE1 protein levels, APP processing and Aβ generation; BACE1 accumulation in response to Aβ or apoptosis requires SUMO1. Co-immunoprecipitation of SUMO1 and BACE1, gain- and loss-of-function experiments, APP processing and Aβ measurement, APPswe transgenic mouse brain analysis Neurobiology of aging Medium 22975420
2012 GGA1 and GGA3 synergistically regulate BACE1 protein levels in vivo; GGA1 is a novel caspase-3 substrate depleted after TBI; GGA3 haploinsufficiency sustains elevated BACE1 and Aβ after brain injury; GGA1 and GGA3 are depleted while BACE1 is elevated in AD brains. GGA3 knockout mice, GGA1 siRNA silencing in neurons, traumatic brain injury mouse model, AD postmortem brain analysis, western blot, Aβ ELISA The Journal of neuroscience High 22836275
2012 ATase1 and ATase2, two ER-based acetyl-CoA:lysine acetyltransferases, regulate BACE1 protein levels; pharmacological inhibition of ATase1/ATase2 down-regulates BACE1 expression and activity. ATase inhibitor compounds, western blot for BACE1 in neurons and glial cells, Aβ measurement, competitive and non-competitive inhibition analysis The Journal of biological chemistry Medium 22267734
2013 Activity-induced convergence of APP and BACE-1 in acidic recycling endosomes occurs via clathrin-dependent endocytosis; in basal conditions APP (in Golgi-derived vesicles) and BACE-1 (in acidic recycling endosomes) are largely segregated in hippocampal neurons; neuronal activity routes APP into BACE-1-positive endosomes. Live imaging of dendritic vesicle dynamics in cultured hippocampal neurons, pharmacological inhibition of clathrin-dependent endocytosis, comparison of APP/BACE-1 vesicle partitioning in control vs. AD brains Neuron High 23931995
2013 BACE1 directly cleaves membrane-anchored Jagged1 (Jag1); loss of BACE1 reduces Jag1 shedding, upregulating Notch signaling via juxtacrine interactions, and causing increased astrogenesis with decreased neurogenesis in hippocampi of BACE1-null mice during early development. BACE1 knockout mice, BACE1 overexpression in cell lines, biochemical cleavage assays for Jag1, Notch signaling readouts, BrdU/cell fate marker analysis in hippocampus Cell reports High 23831026
2014 BACE1 directly cleaves human contactin-2 near its GPI membrane linker domain; BACE1 activity tightly regulates contactin-2 surface levels in CHO cells and primary neurons; contactin-2 mutation at the BACE1 cleavage site (1008MM/AA) dramatically impairs soluble contactin-2 release. BACE1 overexpression in CHO-contactin-2 cells, pharmacological BACE1 inhibition, cleavage site mutagenesis (MM/AA), surface biotinylation, immunofluorescence, primary neuron experiments Molecular neurodegeneration High 24405708
2014 Reticulon 3 (RTN3) deficiency increases BACE1 protein levels and enhances BACE1-mediated APP processing at the β-secretase site; RTN3 normally interacts with BACE1 and negatively regulates BACE1 activity; RTN3-null mice in Alzheimer's background show facilitated amyloid deposition. RTN3 knockout mice, biochemical analysis of BACE1 levels and activity, APP β-secretase cleavage product measurement, Alzheimer's model crosses The Journal of neuroscience High 25319692
2015 APP and BACE-1 interact in both biosynthetic and endocytic compartments, particularly along recycling microdomains such as dendritic spines and presynaptic boutons; APP and BACE-1 are cotransported along axons; the Alzheimer's disease-protective 'Icelandic' APP mutation greatly attenuates APP-BACE-1 interactions. Fluorescence complementation assay for in cellulo APP-BACE-1 interactions, live imaging, internalized APP fate tracking in hippocampal neurons Nature neuroscience High 26642089
2015 BACE1 and ADAM10 are enriched in synaptic vesicles isolated from rat brain; ADAM10 activity is also detectable in synaptic vesicles along with enriched APP-CTFs, indicating that initial APP cleavage occurs at the synapse in synaptic vesicles. Controlled-pore glass chromatography for synaptic vesicle isolation, western blotting, in situ proximity ligation assay for ADAM10/BACE1 colocalization with synaptophysin in primary hippocampal neurons Journal of neurochemistry Medium 26296617
2015 BACE1 deletion impairs sciatic nerve remyelination; both axonal and Schwann cell BACE1 are equally required for optimal remyelination; nerve injury induces BACE1 transcription in Schwann cells; abolished Nrg1 (type I) cleavage in BACE1-null Schwann cells contributes to impaired remyelination. Nerve segment transplant/swap experiments between BACE1-null and wild-type mice, BACE1 transcription analysis in Schwann cells, Nrg1 isoform cleavage analysis The Journal of neuroscience High 25740511
2015 sAPPα is a potent endogenous inhibitor of BACE1, likely acting via an allosteric mechanism; sAPPβ (which lacks 16 C-terminal amino acids) adopts a different structure and does not inhibit BACE1. In vitro BACE1 inhibition assays with sAPPα and sAPPβ, small-angle X-ray scattering for structural analysis, inhibition kinetics analysis Journal of Alzheimer's disease High 26401691
2016 Autophagy-lysosomal pathway regulates BACE1 trafficking and degradation; induction of autophagy enhances BACE1 turnover dependent on lysosomal activity; BACE1 co-migrates with autophagic vacuoles along axons; in APP mutant transgenic neurons, autophagic vacuole-associated BACE1 accumulates in distal axons, increasing local APP β-cleavage; Snapin-enhanced retrograde transport facilitates BACE1 delivery to lysosomes. Autophagy induction/inhibition, live imaging of BACE1-autophagic vacuole co-migration in axons, BACE1 degradation assays, APP transgenic mouse model analysis, Snapin overexpression The Journal of biological chemistry High 28028177
2017 GGA1 mediates signal-dependent sorting of BACE1 from early to recycling endosomes; phosphorylation of S498 within the DISLL motif of BACE1 cytoplasmic tail by JNK enhances exit from early endosomes via GGA1 and retromer; the phosphomimetic S498D mutant shows faster recycling and reduced Aβ production compared to non-phosphorylatable S498A. BACE1 S498D/S498A phosphomimetic mutants, siRNA knockdown of SNX4, GGA1, retromer components, endosomal trafficking assays, Aβ production measurement, primary neuron experiments Molecular biology of the cell High 29142073
2017 p75 neurotrophin receptor interacts with BACE1; this interaction is enhanced by Aβ; p75 and Aβ together increase colocalization of BACE1 and APP in early endosomes; JNK-mediated phosphorylation of APP-Thr668 and BACE1-Ser498 in the presence of Aβ and p75 may drive this endosomal localization. Co-immunoprecipitation of p75 and BACE1, immunofluorescence colocalization, phosphorylation analysis (JNK inhibitors), early endosome fractionation in cortical neurons Journal of neurochemistry Medium 28869759
2019 BACE1-AS (antisense lncRNA) functions as a competing endogenous RNA (ceRNA) by sequestering BACE1-targeting miRNAs, preventing BACE1 mRNA degradation; BACE1-AS knockdown increases BACE1-targeting miRNAs and reduces BACE1 expression. BACE1-AS overexpression and siRNA knockdown, miRNA level measurement, BACE1 mRNA stability assays, Aβ measurement Journal of chemical neuroanatomy Medium 30959172
2019 MMP13 inhibition reduces BACE1 protein levels via PI3K signaling and eIF4B-mediated translational regulation (at eIF4B S422); this effect is independent of BACE1 gene transcription and protein degradation, and requires the BACE1 5'UTR. Small molecule screen with BACE1 promoter/5'UTR-luciferase reporter, eIF4B mutagenesis (S422R), BACE1 5'UTR deletion, PI3K inhibitor, hippocampal Mmp13 knockdown in APPswe/PS1E9 mice, Aβ measurement Brain High 30596903
2020 AP-2 (clathrin adaptor complex-2) controls BACE1 endosomal trafficking and lysosomal delivery independently of its role in APP endocytosis; conditional AP-2 KO causes BACE1 accumulation in late endosomes and autophagosomes, increasing Aβ production; AP-2 is decreased in iPSC-derived neurons from late-onset AD patients. Conditional AP-2 knockout mice, iPSC-derived AD neurons, BACE1 trafficking analysis by immunofluorescence/fractionation, Aβ production measurement, BACE1 deletion rescue of synapse loss EMBO reports High 32323475
2022 BACE1 deficiency in microglia (5xFAD mice) reduces amyloid plaques through enhanced Aβ clearance (phagocytosis), not through changes in APP processing; microglial BACE1 deletion enhances autophagolysosmal function and metabolic reprogramming via PI3K-mTOR-HIF-1α signaling; unlike global BACE1 deletion, microglial-specific deletion does not reduce long-term potentiation. Microglial-specific Bace1 conditional KO in 5xFAD mice, single-cell RNA-seq of astrocytes/microglia, plaque quantification, LTP electrophysiology, phagocytosis assays, mTOR pathway analysis Science advances High 35857844
2023 BACE1 in astrocytes cleaves insulin receptors (IR); BACE1 deficiency abolishes IR cleavage and enhances expression of Clusterin (CLU) and Cxcl14, boosting Aβ uptake and degradation; astrocyte-specific Bace1 KO in 5xFAD mice attenuates cortical Aβ plaque load through enhanced clearance. Single-cell RNA-seq of purified astrocytes from Bace1 KO mice, astrocyte-specific conditional KO (Bace1fl/fl;Gfap-cre) in 5xFAD mice, siRNA knockdown of CLU, Aβ uptake/degradation assays, western blot for IR cleavage products Molecular neurodegeneration High 37143090
2004 Human BACE forms homodimers in brain tissue stabilized by non-disulfide, non-salt-sensitive intermolecular interactions; the soluble ectodomain exists only as monomer; inactivation of the C-terminal active site (D289A mutant) does not abolish overall enzyme activity, suggesting the enzyme may act as a dimer with the N-terminal active site remaining functional. Biochemical analysis of human brain tissue, denaturing/non-denaturing gel analysis, active site mutagenesis (D289A), colocalization of APP and BACE in cells expressing endogenous BACE The Journal of biological chemistry Medium 15247262
2003 Presenilin-1 (PS1) directly binds BACE1; PS1 preferentially binds immature BACE1 and may act as a functional regulator of BACE1 maturation or activity; interaction confirmed by Co-IP and colocalization in human cultured cells. Yeast two-hybrid, co-immunoprecipitation, colocalization in human cultured cells Neurobiology of disease Medium 12901838
2012 Sorting nexin 12 (SNX12) interacts with BACE1 and regulates its endocytosis; SNX12 downregulation accelerates BACE1 endocytosis and decreases cell surface BACE1, increasing BACE1-mediated APP processing and Aβ generation without affecting in vitro β-secretase activity. Co-immunoprecipitation of SNX12 and BACE1, SNX12 overexpression/knockdown, cell surface BACE1 measurement, Aβ/sAPPβ/APP-CTF quantification, γ-secretase activity assay Molecular neurodegeneration Medium 22709416

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. The Journal of clinical investigation 373 23202730
2002 Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiology of disease 335 12270690
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 254 17576410
2004 Structure-based design of potent and selective cell-permeable inhibitors of human beta-secretase (BACE-1). Journal of medicinal chemistry 251 15588077
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 165 15059975
2009 Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PloS one 162 20041192
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
2008 Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 147 18413858
2015 Visualizing APP and BACE-1 approximation in neurons yields insight into the amyloidogenic pathway. Nature neuroscience 145 26642089
2012 Oxidative stress increases BACE1 protein levels through activation of the PKR-eIF2α pathway. Biochimica et biophysica acta 144 22306812
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 129 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
2008 NFkappaB-dependent control of BACE1 promoter transactivation by Abeta42. The Journal of biological chemistry 115 18263584
2012 Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. The Journal of neuroscience : the official journal of the Society for Neuroscience 109 22895721
2014 Pharmacological inhibition of BACE1 impairs synaptic plasticity and cognitive functions. Biological psychiatry 107 25599931
2011 Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination. The Journal of biological chemistry 101 21576249
2011 Amyloid-β production: major link between oxidative stress and BACE1. Neurotoxicity research 98 22002808
2017 Role of BACE1 in Alzheimer's synaptic function. Translational neurodegeneration 93 28855981
2016 Versatility of the Curcumin Scaffold: Discovery of Potent and Balanced Dual BACE-1 and GSK-3β Inhibitors. Journal of medicinal chemistry 93 26696252
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 90 26710318
2010 Ubiquitin regulates GGA3-mediated degradation of BACE1. The Journal of biological chemistry 86 20484053
2006 Progress toward the discovery and development of efficacious BACE inhibitors. Current opinion in drug discovery & development 78 17117686
2004 Translational regulation of BACE-1 expression in neuronal and non-neuronal cells. Nucleic acids research 76 15034149
2012 BACE1 in Alzheimer's disease. Clinica chimica acta; international journal of clinical chemistry 75 22926063
2007 Mitochondrial respiratory inhibition and oxidative stress elevate beta-secretase (BACE1) proteins and activity in vivo in the rat retina. Experimental brain research 72 17429617
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
2009 Function, regulation and therapeutic properties of beta-secretase (BACE1). Seminars in cell & developmental biology 70 19429494
2022 BACE1: More than just a β-secretase. Obesity reviews : an official journal of the International Association for the Study of Obesity 68 35119166
2014 High activities of BACE1 in brains with mild cognitive impairment. The American journal of pathology 68 24332014
2004 Human BACE forms dimers and colocalizes with APP. The Journal of biological chemistry 67 15247262
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 64 30959172
2015 ADAM10 and BACE1 are localized to synaptic vesicles. Journal of neurochemistry 63 26296617
2009 Cell biology, regulation and inhibition of beta-secretase (BACE-1). The FEBS journal 61 19292866
2019 New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorganic & medicinal chemistry letters 60 30709653
2016 Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Scientific reports 60 26912421
2022 Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance. Science advances 59 35857844
2017 The physical approximation of APP and BACE-1: A key event in alzheimer's disease pathogenesis. Developmental neurobiology 59 29106038
2016 Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation. The Journal of biological chemistry 57 28028177
2012 Depletion of GGA1 and GGA3 mediates postinjury elevation of BACE1. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 22836275
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
2011 Amyloid-β₄₂ activates the expression of BACE1 through the JNK pathway. Journal of Alzheimer's disease : JAD 53 21897006
2012 SUMO1 modulates Aβ generation via BACE1 accumulation. Neurobiology of aging 51 22975420
2010 Inhibition of BACE1 for therapeutic use in Alzheimer's disease. International journal of clinical and experimental pathology 51 20661410
2010 BACE: Therapeutic target and potential biomarker for Alzheimer's disease. The international journal of biochemistry & cell biology 51 20817005
2009 Cholinesterase and BACE1 inhibitory diterpenoids from Aralia cordata. Archives of pharmacal research 51 19898803
2008 Impact of cholesterol level upon APP and BACE proximity and APP cleavage. Biochemical and biophysical research communications 51 18374657
2017 GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Aβ production. Molecular biology of the cell 50 29142073
2012 Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1 (BACE1) inhibitors: conformational constraint to favor a bioactive conformation. Journal of medicinal chemistry 48 22989333
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 46 30596903
2009 Mutant presenilin 1 increases the expression and activity of BACE1. The Journal of biological chemistry 46 19196715
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
2006 Human beta-secretase (BACE) and BACE inhibitors: progress report. Current topics in medicinal chemistry 45 16712492
2005 Progress in the discovery of BACE inhibitors. Current pharmaceutical design 45 16250843
2020 AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons. EMBO reports 44 32323475
2019 The effect of BACE1-AS on β-amyloid generation by regulating BACE1 mRNA expression. BMC molecular biology 43 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
2006 Heparin activates beta-secretase (BACE1) of Alzheimer's disease and increases autocatalysis of the enzyme. Biochemistry 43 16716081
2005 Biochemical and cell-based assays for characterization of BACE-1 inhibitors. Analytical biochemistry 41 15958191
2004 Beta-secretase BACE1 is differentially controlled through muscarinic acetylcholine receptor signaling. Journal of neuroscience research 40 15211591
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
2021 Concatenation of molecular docking and molecular simulation of BACE-1, γ-secretase targeted ligands: in pursuit of Alzheimer's treatment. Annals of medicine 36 34889159
2012 Lysophosphatidic acid induces increased BACE1 expression and Aβ formation. Biochimica et biophysica acta 36 23036978
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 35 29632166
2003 Presenilin-1 interacts directly with the beta-site amyloid protein precursor cleaving enzyme (BACE1). Neurobiology of disease 35 12901838
2003 Dehydroepiandrosterone reduces expression and activity of BACE in NT2 neurons exposed to oxidative stress. Neurobiology of disease 35 14572450
2012 Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation. The Journal of biological chemistry 34 22267734
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 33 33862517
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
2023 BACE1 regulates expression of Clusterin in astrocytes for enhancing clearance of β-amyloid peptides. Molecular neurodegeneration 31 37143090
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
2011 Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1). The Journal of neuroscience : the official journal of the Society for Neuroscience 30 22049418
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
2018 Multifunctional Donepezil Analogues as Cholinesterase and BACE1 Inhibitors. Molecules (Basel, Switzerland) 28 30544832
2009 Design and synthesis of cell potent BACE-1 inhibitors: structure-activity relationship of P1' substituents. Bioorganic & medicinal chemistry letters 28 19811916
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
2018 Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP-2 and BACE-1 activities, and the modulation of APP trafficking. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 30332299
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 p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis. Journal of neurochemistry 25 28869759