CoChat
Sign Up
Cited by 694Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

The β-Secretase BACE1 in Alzheimer’s Disease

Open access
Hampel, Harald, Vassar, Robert, De Strooper, Bart, Hardy, John, Willem, Michael, Singh, Neeraj, Zhou, John, Yan, Riqiang +18 more·2021·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.02.001PMC PMC7533042
Open this paper in CoChat — free accountOpen PDF

Abstract

, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer's disease (AD). BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology. Therefore, BACE1 is a prime drug target for slowing down Aβ production in early AD. Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis. Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes. Despite BACE1 inhibitor clinical trials conducted so far being discontinued for futility or safety reasons, BACE1 remains a well-validated therapeutic target for AD. A safe and efficacious compound with high substrate selectivity as well as a more accurate dose regimen, patient population, and disease stage may yet be found. Further research should focus on the role of Aβ and BACE1 in physiological processes and key pathophysiological mechanisms of AD. The functions of BACE1 and the homologue BACE2, as well as the biology of Aβ in neurons and glia, deserve further investigation. Cellular and molecular studies of BACE1 and BACE2 knockout mice coupled with biomarker-based human research will help elucidate the biological functions of these important enzymes and identify their substrates and downstream effects. Such studies will have critical implications for BACE1 inhibition as a therapeutic approach for AD.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2020.02.001

Cites

139 of 139 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 158 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Besides APP, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis.

    “Besides the amyloidogenic pathway, BACE1 has other substrates that may be important for synaptic plasticity and synaptic homeostasis.”
    • Also stated in: § Synaptic Substrates · boosted
      “Among BACE1 substrates, NRG1 (neuregulin 1), SEZ6 (seizure-related protein 6), and CHL1 (close homologue of neural cell adhesion molecule L1) are known to have important neuronal functions and merit further discussion given the recent reports that BACE1 blockade in patients causes cognitive worsening.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Willem, 2006, Control of peripheral nerve myelination by the beta-secretase BACE1, Science source

      Not checked in the free run.

    • cites [71] Pigoni, 2016, Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons, Mol Neurodegener source

      Not checked in the free run.

  • Premisecitation

    The A673T mutation is associated with 20% to 30% lower soluble APPβ levels compared with controls.

    “In particular, the A673T mutation is associated with a different BACE1 recognition motif at the position P2 (A673T), resulting in 20% to 30% lower soluble APPβ (sAPPβ) levels compared with control subjects (12,13).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Jonsson, 2012, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline, Nature source

      Not checked in the free run.

    • cites [13] Martiskainen, 2017, Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers, Ann Neurol source

      Not checked in the free run.

  • Interpretationreasoning

    The elevation of BACE1 concentration and activity in AD supports the hypothesis that BACE1 has a critical role in AD pathophysiology.

    “thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology.”
    Quote in the paperSubstantial claim
  • Premisecitation

    All BACE inhibitors tested in randomized clinical trials were discontinued for futility or safety reasons.

    “All BACE inhibitors investigated in randomized clinical trials were discontinued for either futility or safety reasons.”
    • Also stated in: § HUMAN CLINICAL TRIALS WITH BACE INHIBITORS: A SCHEMATIC OVERVIEW · plain
      “A Phase 3 trial of verubecestat conducted in mild to moderate patients with AD (EPOCH) was terminated owing to futility (96).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [96] Egan, 2018, Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease, N Engl J Med source

      Not checked in the free run.

    • cites [97] Henley, 2019, Preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease, N Engl J Med source

      Not checked in the free run.

    • cites [98] Strobel

      Not checked in the free run.

    • cites [99] Albert C Lo, 2018, Results from the phase 2 NAVIGATE-AD clinical trial evaluating LY3202626 BACE inhibitor in patients with mild Alzheimer’s disease dementia, CTAD (Clinical Trials on Alzheimer's Disease) 2018, Abstract LB1

      Not checked in the free run.

    • cites [100] 2019

      Not checked in the free run.

  • Premisecitation

    Germline and adult conditional BACE1 knockout mice show complex neurological phenotypes.

    “Indeed, germline and adult conditional BACE1 knockout mice display complex neurological phenotypes.”
    • Also stated in: § Synaptic Substrates · plain
      “Lack of BACE1 was also reported to cause sensorimotor impairments, seizures, schizophrenia-like phenotypes, and retinal pathology (65–67).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [65] Kobayashi, 2008, BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer’s disease, Neurobiol Aging source

      Not checked in the free run.

    • cites [66] Savonenko, 2008, Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [67] Cai, 2012, β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment, EMBO Mol Med source

      Not checked in the free run.

  • May combine two claims. 40
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    BACE1 concentrations and activity rates are elevated in AD brains and body fluids.

    “BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology.”
    • Also stated in: § Amyloidogenesis · plain
      “High BACE1 enzymatic activity was found in human AD brain extracts, which is consistent with the finding that neurons produce the highest levels of Aβ (3,45).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Vassar, 1999, Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE, Science source

      Not checked in the free run.

    • cites [45] Haass, 1992, Amyloid beta-peptide is produced by cultured cells during normal metabolism, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 is the β-secretase that cleaves APP and, together with γ-secretase, produces Aβ species.

    “BACE1 is the β-secretase enzyme that cleaves the transmembrane APP and, together with γ-secretase, generates Aβ species that in AD form increasingly large and conformationally complex soluble regionally deposited brain aggregates”
    • Also stated in: § Amyloidogenesis · boosted
      “BACE1 has been extensively studied in the context of brain amyloidogenesis and proven to be directly involved in Aβ production based on data from several knockout (KO) mouse models (41–43).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Luo, 2001, Mice deficient in BACE1, the Alzheimer’s beta-secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci source

      Not checked in the free run.

    • cites [42] Dominguez, 2005, Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice, J Biol Chem source

      Not checked in the free run.

    • cites [43] Harrison, 2003, BACE1 (beta-secretase) transgenic and knockout mice: Identification of neurochemical deficits and behavioral changes, Mol Cell Neurosci source

      Not checked in the free run.

    • Rests on an assumption: BACE1 cleavage of APP is the rate-limiting step for Aβ production.

  • May combine two claims.

    Premisecitation

    The Swedish APP mutation increases β-site processing 10- to 50-fold and causes early onset AD.

    “The most prominent one is the Swedish mutation (K670M671 to N670L671 mutation at the cleavage P2-P1 subsite), which increases processing of APP at the β site by 10- to 50-fold and causes early onset of AD (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Mullan, 1992, A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid, Nat Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The A673T mutation confers intrinsic biochemical resistance to BACE1 cleavage, resulting in less Aβ production and less aggregation-prone peptides.

    “Intriguingly, an Ala residue at the cleavage P3, subsite mutated to Thr (A673T) in APP confers an intrinsic biochemical resistance to cleavage by BACE1, resulting in less Aβ production overall and also in generation of peptides that are less prone to aggregation (12,13).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Jonsson, 2012, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline, Nature source

      Not checked in the free run.

    • cites [13] Martiskainen, 2017, Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers, Ann Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The APP A673T variant is more frequent in Icelandic and Scandinavian populations and provides resilience against age-related brain Aβ deposition and AD.

    “Whole-genome sequencing studies identified a genetic variant of APP, significantly more frequent in Icelandic and Scandinavian populations, that provides resilience against age-related brain Aβ deposition and AD (12,13).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Jonsson, 2012, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline, Nature source

      Not checked in the free run.

    • cites [13] Martiskainen, 2017, Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers, Ann Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP is highly expressed in neurons and abundant at the synapse.

    “APP is a type I transmembrane protein and is highly expressed in neurons and abundant at the synapse (48–52).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [48] Kim, 1995, Selective localization of amyloid precursor-like protein 1 in the cerebral cortex postsynaptic density, Brain Res Mol Brain Res source

      Not checked in the free run.

    • cites [49] Rodrigues, 2014, Synaptic and sub-synaptic localization of amyloid-β protein precursor in the rat hippocampus, J Alzheimers Dis source

      Not checked in the free run.

    • cites [50] Rice, 2019, Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission, Science source

      Not checked in the free run.

    • cites [51] Hoe, 2009, The effects of amyloid precursor protein on postsynaptic composition and activity, J Biol Chem source

      Not checked in the free run.

    • cites [52] Wilhelm, 2014, Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Soluble APP is a GABAB ligand that modulates synaptic transmission.

    “Soluble APP is a GABAB (gammaaminobutyric acid type B) ligand that modulates synaptic transmission (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Rice, 2019, Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRG1, SEZ6, and CHL1 are BACE1 substrates with important neuronal functions.

    “Among BACE1 substrates, NRG1 (neuregulin 1), SEZ6 (seizure-related protein 6), and CHL1 (close homologue of neural cell adhesion molecule L1) are known to have important neuronal functions and merit further discussion given the recent reports that BACE1 blockade in patients causes cognitive worsening.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Willem, 2006, Control of peripheral nerve myelination by the beta-secretase BACE1, Science source

      Not checked in the free run.

    • cites [71] Pigoni, 2016, Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons, Mol Neurodegener source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ubiquitination of BACE1 promotes its lysosomal degradation and is impaired in AD.

    “ubiquitination of BACE1 promotes its degradation in the lysosome and is impaired in AD (37,38).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Kang, 2010, Ubiquitin regulates GGA3-mediated degradation of BACE1, J Biol Chem source

      Not checked in the free run.

    • cites [38] Kang, 2012, BACE1 protein endocytosis and trafficking are differentially regulated by ubiquitination at lysine 501 and the Di-leucine motif in the carboxyl terminus, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 mRNA levels are significantly increased in 3×Tg mouse brains and in AD peripheral blood mononuclear cells, are much less elevated in MCI, and this increase is linked to H3 acetylation facilitating BACE1 promoter accessibility.

    “BACE1 messenger RNA levels are significantly increased in 3×Tg mouse brains and in peripheral blood mononuclear cells from patients with AD but are much less elevated in mild cognitive impairment (MCI) compared with control subjects, and this increase is linked to H3 acetylation facilitating the accessibility of the BACE1 promoter (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Marques, 2012, Epigenetic regulation of BACE1 in Alzheimer’s disease patients and in transgenic mice, Neuroscience source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BACE1 requires a low acidic environment, ideally around pH 4.5, for optimal proteolytic activity.

    “Overall, as an aspartyl protease, BACE1 requires low acidic environments to reach optimal proteolytic activity, ideally at ~pH 4.5 (39,40).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [39] Tomasselli, 2003, Employing a superior BACE1 cleavage sequence to probe cellular APP processing, J Neurochem source

      Not checked in the free run.

    • cites [40] Turner, 2002, Specificity of memapsin 1 and its implications on the design of memapsin 2 (beta-secretase) inhibitor selectivity, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lack of BACE1 causes sensorimotor impairments, seizures, schizophrenia-like phenotypes, and retinal pathology.

    “Lack of BACE1 was also reported to cause sensorimotor impairments, seizures, schizophrenia-like phenotypes, and retinal pathology (65–67).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [65] Kobayashi, 2008, BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer’s disease, Neurobiol Aging source

      Not checked in the free run.

    • cites [66] Savonenko, 2008, Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [67] Cai, 2012, β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment, EMBO Mol Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inducing autophagy in mutant human neurons increases BACE1 retention in distal axons and enhances β-cleavage of APP.

    “Inducing autophagy in mutant human neurons augments retention of BACE1 in distal axons by autophagy, leading to enhanced β-cleavage of APP (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Feng, 2017, Autophagy-mediated regulation of BACE1 protein trafficking and degradation, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 cleavage of NRG1 is essential for central and peripheral myelination and for muscle spindle formation and maintenance.

    “BACE1 cleavage of NRG1 is essential for myelination in the central nervous system and peripheral nerves as well as for muscle spindle formation and maintenance (70).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Willem, 2006, Control of peripheral nerve myelination by the beta-secretase BACE1, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phosphorylation of BACE1 at Ser498 regulates intracellular trafficking between endosome and plasma membrane but has minimal or no effect on Aβ levels.

    “BACE1 undergoes phosphorylation at both Ser498 and Thr252, but phosphorylation at the Ser498 residue appears to regulate intracellular trafficking by shuttling/recycling BACE1 between endosome and plasma membrane (33). This modification at Ser498 has minimal or no effect on Aβ levels (34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Walter, 2001, Phosphorylation regulates intracellular trafficking of beta-secretase, J Biol Chem source

      Not checked in the free run.

    • cites [34] Pastorino, 2002, The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total Aβ, Mol Cell Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP function remains elusive, but studies implicate it in dendritic spine maintenance, neurotransmission, synaptic plasticity, and excitation/inhibition balance.

    “Its function remains elusive, although studies implicated it in maintenance of dendritic spines (53), neurotransmission (54), synaptic plasticity (55–58), and maintenance of excitation/inhibition balance (58).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [53] Jung, 2012, Role of APP for dendritic spine formation and stability, Exp Brain Res source

      Not checked in the free run.

    • cites [54] Wang, 2014, The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons, J Neurosci source

      Not checked in the free run.

    • cites [55] Dawson, 1999, Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the beta-amyloid precursor protein, Neuroscience source

      Not checked in the free run.

    • cites [56] Seabrook, 1999, Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein, Neuropharmacology source

      Not checked in the free run.

    • cites [57] Yang, 2009, Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity, J Neurosci source

      Not checked in the free run.

    • cites [58] Born, 2014, Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of Alzeimer’s disease, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The A673T mutation appears to protect against AD and age-related cognitive decline by suppressing APP cleavage at the β site.

    “The A673T mutation appears to protect against AD and age-related cognitive decline as a result because of suppressed cleavage of APP at the β site”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Jonsson, 2012, A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline, Nature source

      Not checked in the free run.

    • cites [13] Martiskainen, 2017, Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers, Ann Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 activity is regulated by posttranslational modifications as well as by expression level.

    “BACE1 activity is regulated not only at the expression level but also by posttranslational modification.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [31] Bao, 2018, BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [32] Vetrivel, 2009, Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts, J Biol Chem source

      Not checked in the free run.

    • cites [33] Walter, 2001, Phosphorylation regulates intracellular trafficking of beta-secretase, J Biol Chem source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Doses selected for prior and current BACE1 inhibitor studies may be too high, targeting more than 50% BACE1 inhibition and causing unwanted side effects, while lower inhibition could have been therapeutically active.

    “Dose levels selected for all prior and current ongoing studies may be too high, targeting more than 50% inhibition of BACE1, leading to unwanted side effects, while potentially lower levels of inhibition could have been therapeutically active.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In pancreatic β cells, Tmem27 and islet amyloid polypeptide are proposed BACE2 substrates.

    “In pancreatic β cells, the proproliferative plasma membrane protein Tmem27 and islet amyloid polypeptide are proposed BACE2 substrates (75,76).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Rulifson, 2016, Identification of human islet amyloid polypeptide as a BACE2 substrate, PLoS One source

      Not checked in the free run.

    • cites [76] Alcarraz-Vizan, 2017, BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression, Cell Mol Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inhibiting BACE1 lowers Aβ production, but combined BACE2 inhibition blocks processing of other substrates with potential negative impact, changing the benefit/risk ratio.

    “Inhibiting BACE1 lowers Aβ production, but in combination with BACE2 inhibition the processing of a number of other substrates are blocked with potential negative impact, changing the benefit/risk ratio (see also Supplemental Table S2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplemental Table S2

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human postmortem studies show high BACE2 expression and strong correlation with BACE1 expression in neurons and astrocytes of AD patients but not controls.

    “Human postmortem studies showed high expression levels of BACE2 and strong correlation with BACE1 expression in neurons and astrocytes of patients with AD but not of control subjects (77).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Holler, 2012, BACE2 expression increases in human neurodegenerative disease, Am J Pathol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BACE2 processes PMEL in pigment cells.

    “BACE2 also processes the PMEL (pigment cell–specific melanocyte protein) in pigment cells (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Rochin, 2013, BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Some detrimental effects during initial treatment may be caused by acute synaptic impairment via BACE1 inhibition of substrates other than APP and should be assessed for reversibility after treatment stops.

    “Some detrimental effects were induced during the initial phase of treatment and were irrespective of disease stage. It is conceivable that these negative effects may be caused by acute synaptic impairment via BACE1 inhibition for some substrates other than APP and should be assessed for reversibility after off-treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    BACE1 inhibitors started before tau pathology spreads may represent the most suitable path to pursue.

    “If so, BACE1 inhibitors started prior to the spreading of tau pathology may represent the most suitable path to pursue (108).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Zhu, 2018, Consequences of pharmacological BACE inhibition on synaptic structure and function, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 biomarkers are associated with other core CSF and neuroimaging AD biomarkers and with APOE ε4 allele presence.

    “Some studies also showed an association between BACE1 biomarkers and other core CSF and neuroimaging biomarkers of AD as well as the presence of apolipoprotein E (APOE) ε4 allele (79–85).”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [79] Mulder, 2010, BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology, J Alzheimers Dis source

      Not checked in the free run.

    • cites [80] Zhong, 2007, Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [81] Ewers, 2008, Increased CSF-BACE 1 activity is associated with ApoE-epsilon 4 genotype in subjects with mild cognitive impairment and Alzheimer’s disease, Brain source

      Not checked in the free run.

    • cites [82] Wu, 2012, Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer’s disease, J Neurosci Res source

      Not checked in the free run.

    • cites [83] Zetterberg, 2008, Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease, Arch Neurol source

      Not checked in the free run.

    • cites [84] Ewers, 2011, Increased CSF-BACE1 activity associated with decreased hippocampus volume in Alzheimer’s disease, J Alzheimers Dis source

      Not checked in the free run.

    • cites [85] Molinuevo, 2018, Current state of Alzheimer’s fluid biomarkers, Acta Neuropathol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BACE2 is more prominently expressed in colon, kidney, and pancreas.

    “Much less is known about the brain-relevant substrates and functions of the sister secretase BACE2 that is more prominently expressed in the colon, kidney, and pancreas (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Voytyuk, 2018, BACE2 distribution in major brain cell types and identification of novel substrates, Life Sci Alliance source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More than 40 BACE1 substrates are known, and BACE inhibitors may block one or more of them, causing functional consequences.

    “there are more than 40 known BACE1 substrates (see Table 2), and BACE inhibitors may block one or more of them, causing functional consequences.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some studies show no acceptable diagnostic performance of BACE1 biomarkers or no association with established AD biomarkers.

    “By contrast, some studies showed no acceptable diagnostic performance of BACE1 biomarkers (90–92) or no association between them and AD established biomarkers.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [90] Savage, 2015, Soluble BACE-1 activity and sAβPPβ concentrations in Alzheimer’s disease and age-matched healthy control cerebrospinal fluid from the Alzheimer’s Disease Neuroimaging Initiative-1 baseline cohort, J Alzheimers Dis source

      Not checked in the free run.

    • cites [91] Perneczky, 2014, Cerebrospinal fluid BACE1 activity and markers of amyloid precursor protein metabolism and axonal degeneration in Alzheimer’s disease, Alzheimers Dement source

      Not checked in the free run.

    • cites [92] Wu, 2008, Decrease in age-adjusted cerebrospinal fluid beta-secretase activity in Alzheimer’s subjects, Clin Biochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Different single nucleotide polymorphism variations at the BACE2 locus are associated with AD risk and altered Aβ processing.

    “Huentelman et al. reported that different single nucleotide polymorphism variations at the BACE2 locus are associated with AD risk and altered Aβ processing (78).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Huentelman, 2019, Common BACE2 polymorphisms are associated with altered risk for Alzheimer’s disease and CSF amyloid biomarkers in APOE ε4 non-carriers, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There are enough promising data to support developing BACE1 biomarkers and investigating whether they can enrich the AD biomarker panel and support contexts of use in BACE1 clinical trials.

    “In summary, there are enough promising data to boost development of BACE1 biomarkers and investigate whether they may enrich the current AD biomarkers panel and potentially support different contexts of use in BACE1 clinical trials, including target engagement and proof of mechanism, dose finding, efficacy, and safety monitoring.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Absence of SEZ6 or pharmacological BACE1 inhibition impairs synaptic plasticity; aberrant BACE1 processing of SEZ6 lowers spine density and attenuates hippocampal long-term potentiation.

    “In its absence, achieved by genetic KO of SEZ6 or pharmacological inhibition of BACE1, synaptic plasticity is impaired. In particular, aberrant BACE1 processing of SEZ6 results in lower spine density and attenuated long-term potentiation in the hippocampus (1,71).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Zhu, 2018, Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6, Biol Psychiatry source

      Not checked in the free run.

    • cites [71] Pigoni, 2016, Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons, Mol Neurodegener source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BACE1 cleavage of CHL1 produces an intracellular membrane-bound C-terminal fragment that influences cytoskeleton dynamics and leads to growth cone collapse upon Sema3A.

    “BACE1 cleavage yields an intracellular membrane-bound C-terminal fragment of CHL1 that is able to influence cytoskeleton dynamics, leading to growth cone collapse on presentation of the Sema3A cue.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Ou-Yang, 2018, Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice, Sci Transl Med source

      Not checked in the free run.

    • cites [73] Wright, 2007, Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The BACE1 target has a good scientific rationale and was properly and extensively validated in experimental AD models before clinical studies.

    “we argue that the target has a good scientific rationale and was properly and extensively validated in experimental models of AD ahead of clinical studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lower BACE1 levels are found in advanced dementia stages of AD, potentially due to advanced neuronal and synaptic loss.

    “Moreover, lower levels of BACE1 were found in advanced dementia stages of AD, potentially owing to advanced neuronal and synaptic loss (93–95).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [93] Alexopoulos, 2018, Cerebrospinal fluid BACE1 activity and sAβPPβ as biomarker candidates of Alzheimer’s disease, Dement Geriatr Cogn Disord source

      Not checked in the free run.

    • cites [94] Rosen, 2012, Cerebrospinal fluid profiles of amyloid β-related biomarkers in Alzheimer’s disease, Neuromolecular Med source

      Not checked in the free run.

    • cites [95] Decourt, 2011, BACE1 as a potential biomarker for Alzheimer’s disease, J Alzheimers Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Clinical-stage BACE compounds had variable selectivity for BACE1 but all also inhibited BACE2 activity.

    “Current compounds tested in the clinic had variable amounts of selectivity for BACE1, but all exerted inhibition of BACE2 activity as well.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Axon guidance abnormalities in the hippocampus persist in adult conditional BACE1 knockout, confirming an important role for BACE1 in adult circuitry architecture as well as developmental functions.

    “Intriguingly, axon guidance abnormalities in the hippocampus persist in the adult conditional KO of BACE1, confirming an important role of the secretase in adult circuitry architecture as well as its established developmental functions (69,72–74).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [69] Zhou, 2012, The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo, J Biol Chem source

      Not checked in the free run.

    • cites [72] Ou-Yang, 2018, Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice, Sci Transl Med source

      Not checked in the free run.

    • cites [73] Wright, 2007, Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon, J Neurosci source

      Not checked in the free run.

    • cites [74] Vassar, 2019, Editorial: Implications for BACE1 inhibitor clinical trials: Adult conditional BACE1 knockout mice exhibit axonal organization defects in the hippocampus, J Prev Alzheimers Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Other Aβ forms besides fibrils and plaques may trigger brain toxicity and contribute to AD synaptic failure.

    “These findings indicated that other forms of Aβ, besides fibrils and plaques, may trigger brain toxicity and contribute to AD-synaptic failure (115,116,118,119).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [115] Nilsberth, 2001, The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation, Nat Neurosci source

      Not checked in the free run.

    • cites [116] Tomiyama, 2008, A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia, Ann Neurol source

      Not checked in the free run.

    • cites [118] O’Nuallain, 2010, Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils, J Neurosci source

      Not checked in the free run.

    • cites [119] Shankar, 2008, Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HEK293 cells treated with KMI-574 show dissociation of BACE1 from lipid rafts to nonraft membranes and reduced BACE1 processing activity.

    “HEK293 cells treated with KMI-574 specifically caused dissociation of BACE1 from lipid raft to nonraft membranes, and BACE1 processing activity was reduced (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Ebina, 2009, Inhibition by KMI-574 leads to dislocalization of BACE1 from lipid rafts, J Neurosci Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The human APP Arctic and E693Δ (Osaka) mutations show an AD type with low cerebral plaque deposition, modest Aβ-PET binding, and higher production of oligomers and protofibrils likely to initiate Aβ toxicity.

    “The recently discovered human APP Arctic (115) and E693Δ (Osaka) (116) mutations show a type of AD with low cerebral deposition of plaques, as indicated by modest Aβ-positron emission tomography radiotracer binding (117) and higher production of oligomers and protofibrils that are likely to be the initiators of Aβ toxicity (115,116,118,119).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [115] Nilsberth, 2001, The “Arctic” APP mutation (E693G) causes Alzheimer’s disease by enhanced Abeta protofibril formation, Nat Neurosci source

      Not checked in the free run.

    • cites [116] Tomiyama, 2008, A new amyloid beta variant favoring oligomerization in Alzheimer’s-type dementia, Ann Neurol source

      Not checked in the free run.

    • cites [117] Scholl, 2012, Low PiB PET retention in presence of pathologic CSF biomarkers in Arctic APP mutation carriers, Neurology source

      Not checked in the free run.

    • cites [118] O’Nuallain, 2010, Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils, J Neurosci source

      Not checked in the free run.

    • cites [119] Shankar, 2008, Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory, Nat Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Emerging evidence encourages a new generation of compounds with ultra APP-selective BACE inhibitory effects.

    “While the research community continues to debate the most plausible biological and pharmacological explanations for BACE1 clinical trial failures, there is emerging evidence encouraging a new generation of compounds with an ultra APP selectivity BACE inhibitory effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    BACE1 is established to play a key role in Aβ homeostasis and may have an important function in synaptic plasticity.

    “In this context, BACE1 is established to play a key role in Aβ homeostasis and may have an important function in synaptic plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    An experimental lithium microdose-release formulation is associated with lower BACE1 gene expression and reduced cerebral Aβ accumulation.

    “Wilson et al. reported that an innovative experimental formulation of lithium microdose release is associated with the lowering of BACE1 gene expression and overall cerebral Aβ accumulation (110)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Wilson, 2017, BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology, Transl Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The failure of several BACE1 inhibitor clinical trials appears to involve insufficient understanding of BACE1 biology and physiology, limited knowledge of AD natural history and optimal treatment stage, and lack of biomarker-based outcomes and end points.

    “The failure of several BACE1 inhibitor clinical trials appears to involve insufficient understanding of BACE1 biology and physiology, limited knowledge of the natural history of AD and the optimal stage of disease at which to treat, and lack of biomarker-based outcomes and end points.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    BACE1-oriented therapies remain a rational and central development area for time-sensitive, mechanism-based preventive strategies for AD.

    “Within this conceptual framework, BACE1-oriented therapies continue to represent a rational and central development area for time-sensitive and effective pathway (mechanism)– based preventive strategies for AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Genetic, epigenetic, and posttranslational factors influence BACE1 expression and enzymatic activity and may explain interindividual heterogeneity in BACE1-related pathophysiology and drug response.

    “During the past 20 years, several key genetic, epigenetic, and posttranslational factors have been established to influence BACE1 gene expression levels and enzymatic activity that may explain interindividual heterogeneity in BACE1-related pathophysiological processes and drug response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    AD mouse models expressing S-palmitoylation-deficient BACE1 show significantly decreased Aβ burden and improved memory function, indicating that BACE1 S-palmitoylation influences Aβ pathogenesis.

    “it was shown that AD mouse models expressing S-palmitoylation-deficient BACE1 had a significant decrease in Aβ burden and improved memory function, indicating that posttranslational S-palmitoylation of BACE1 influences Aβ pathogenesis (32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Vetrivel, 2009, Alzheimer disease Abeta production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts, J Biol Chem source

      Not checked in the free run.

47 of 47

  • The paper relies on this without support.

    BACE1 cleavage of APP is the rate-limiting step for Aβ production.

    “BACE1 cleavage of APP represents the rate-limiting step for Aβ production.”

  • The paper relies on this without support.

    Aβ42 aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer’s disease.

    “including Aβ42, which aggregates into bioactive conformational species and likely initiates toxicity in Alzheimer’s disease (AD).”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • SGK1 maintains stable levels of BACE1 and Cofilin, indicating its influence does not involve promoting the amyloidogenic β pathway.

    “Simultaneously, SGK1 maintains stable levels of BACE1 (β-secretase) and Cofilin, indicating its influence does not involve promoting the amyloidogenic β pathway”

    From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Hampel et al., 2021

    The Amyloidogenesis section identifies BACE1 as the β-secretase involved in Aβ production, but does not address SGK1’s effect on that pathway. Searches for SGK1 and Cofilin found no passage reporting stable levels of either protein or drawing the claimed conclusion about SGK1. Page numbers were unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Strong suppression of amyloid-beta production by BACE inhibition reduced amyloid deposition by about 20% and produced a modest increase in cognitive impairment, probably through unwanted on-target effects.

    “Strong suppression of Aβ production, via BACE inhibition, reduced amyloid deposition by about 20% and resulted in a modest increase in cognitive impairment, probably due to unwanted on-target effects mediated via inhibiting other BACE substrates”

    From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [39]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Glycosylation sites are identified as different residue types

    Minor

    The paper identifies four asparagine (Asn) glycosylation sites, then describes suppressing glycosylation by mutating "these aspartic acid residues." Asparagine and aspartic acid are different residues.

  • A673T is assigned to two cleavage-site positions

    Minor

    The paper places the A673T residue at P3 in one passage and at P2 in another. Both passages describe its position in the BACE1 cleavage-site motif.

  • The enzyme cleaving CTF-β changes between passages

    Minor

    The paper first describes β-secretase as cleaving APP and γ-secretase as participating in Aβ generation. It later says β-secretase cleaves the resulting CTF-β fragment to release Aβ.

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Zhu, 2018, Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6, Biol Psychiatry, 83, 428, 10.1016/j.biopsych.2016.12.023 · DOI · Paper page
  2. Haniu, 2000, Characterization of Alzheimer’s beta-secretase protein BACE: A pepsin family member with unusual properties, J Biol Chem, 275, 21099, 10.1074/jbc.M002095200 · DOI
  3. Albert C Lo, 2018, Results from the phase 2 NAVIGATE-AD clinical trial evaluating LY3202626 BACE inhibitor in patients with mild Alzheimer’s disease dementia, CTAD (Clinical Trials on Alzheimer's Disease) 2018, Abstract LB1, S37
  4. Seeley, 2011, Divergent network connectivity changes in healthy APOE ε4 carriers: Disinhibition or compensation?, Arch Neurol, 68, 1107, 10.1001/archneurol.2011.202 · DOI

Cited by

Sorted by citations

Authors
Hampel, H., Vassar, R., De Strooper, B., Hardy, J., Willem, M., Singh, N., Zhou, J., Yan, R., Vanmechelen, E., De Vos, A., Nisticò, R., Corbo, M., Imbimbo, B. P., Streffer, J., Voytyuk, I., Timmers, M., Tahami Monfared, A. A., Irizarry, M., Albala, B., Koyama, A., Watanabe, N., Kimura, T., Yarenis, L., Lista, S., Kramer, L., & Vergallo, A.
Affiliations
  • Sorbonne Université (FR)
  • Northwestern University (US)
  • UCL Queen Square Institute of Neurology (GB)
  • Ludwig-Maximilians-Universität München (DE)
  • UConn Health (US)
  • ADx NeuroSciences (BE)
  • University of Rome Tor Vergata (IT)
  • Chiesi (Italy) (IT)
  • University of Antwerp (BE)
  • University of Cambridge (GB)
  • Janssen (Belgium) (BE)
  • Eisai (United States) (US)
  • Eisai (Japan) (JP)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Hampel, Harald
  • Vergallo, Andrea
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2021-04
Volume
89
Issue
8
Pages
745-756
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.02.001
PMC
PMC7533042
OpenAlex
W3006119534
Cited by
694
References
139
Citations by year
2026: 98 · 2025: 113 · 2024: 164 · 2023: 123 · 2022: 115 · 2021: 68 · 2020: 12
FWCI
10.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, cc-by-nc)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
  • Lirias (KU Leuven) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • Fanconi Anemia Research Fund
  • Fondation pour la Recherche sur Alzheimer
  • Eli Lilly and Company (20080131921, 20080199966, 20080206797, 20090263822, 20100035286, 20100062463, 20120196300, 7547553, 8298784, 8916388)
  • Pfizer
  • Johnson and Johnson
  • Eisai Incorporated
  • Servier
  • Association Sorbonne Université (ANR-10-IAIHU-06)
  • Agence Nationale de la Recherche
  • AXA Research Fund
  • Roche
  • Biogen
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
BACE1, Alzheimer's disease, beta-secretase, amyloid-beta, BACE1 inhibitors, BACE2, amyloidogenic pathway, synaptic plasticity, therapeutic target, biomarkers
MeSH terms
Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Amyloid Precursor Protein Secretases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review