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Cited by 107Adipokines, Inflammation, and Metabolic DiseasesAlzheimer's disease research and treatmentsRegulation of Appetite and Obesity

The DOI matches its Crossref record; 194 of the 194 references it cites were found in a registry or an index; 6 of the 154 sources its claims cite were checked for support.

BACE1: More than just a β‐secretase

Open access
Taylor, Hannah A., Przemylska, Lena, Clavane, Eva M., Meakin, Paul J.·2022·Obesity Reviews
DOI 10.1111/obr.13430PMC PMC9286785
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Abstract

Summary: β‐site amyloid precursor protein cleaving enzyme‐1 (BACE1) research has historically focused on its actions as the β‐secretase responsible for the production of β‐amyloid beta, observed in Alzheimer's disease. Although the greatest expression of BACE1 is found in the brain, BACE1 mRNA and protein is also found in many cell types including pancreatic β‐cells, adipocytes, hepatocytes, and vascular cells. Pathologically elevated BACE1 expression in these cells has been implicated in the development of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease. In this review, we examine key questions surrounding the BACE1 literature, including how is BACE1 regulated and how dysregulation may occur in disease, and understand how BACE1 regulates metabolism via cleavage of a myriad of substrates. The phenotype of the BACE1 knockout mice models, including reduced weight gain, increased energy expenditure, and enhanced leptin signaling, proposes a physiological role of BACE1 in regulating energy metabolism and homeostasis. Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology. Finally, this review aims to examine the possibility that BACE1 inhibitors could provide a innovative treatment for obesity and its comorbidities.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

BACE1 is best known as the β-secretase producing Aβ in Alzheimer’s disease, but this review argues it also has broad non-neuronal metabolic roles via cleavage of many substrates in insulin, leptin, adipose, vascular, and immune pathways. It proposes that existing BACE1 inhibitors, despite failing in AD trials, might be repurposed for obesity and cardiometabolic disease because weight loss was observed as a side effect.

Key findings

  • BACE1 is a 501-amino-acid type 1 membrane aspartyl protease with five domains, active at optimal pH 4.5, and has nearly 70 identified substrates beyond APP; many are associated with non-neuronal functions including insulin signaling, inflammation, cardiovascular function, and glucose homeostasis.
  • BACE1 knockout/inhibition phenotypes include reduced weight gain, increased energy expenditure, enhanced leptin signaling, and no change in daily food intake, suggesting weight effects occur through energy expenditure; BACE1 knock-in mice display AD-like pathology and systemic diabetes.
  • In clinical trials, Verubecestat reduced cerebrospinal fluid Aβ levels by 63%–81% but did not improve cognition and caused adverse effects including weight loss and decreased appetite; Lanabecestat produced mean weight loss of −1.9 kg in the 50-mg group versus 0 with placebo, with more individuals losing at least 7% weight than placebo.
  • The review links BACE1 to T2D and obesity via insulin receptor cleavage, Aβ-mediated insulin resistance, leptin resistance, BAT differentiation through the Dicer1/miR-328/BACE1 axis, and vascular/immune mechanisms; T2D sufferers have a 50% increased risk of developing AD.

Methods

  • Narrative review synthesizing published literature on BACE1 structure, substrates, transcriptional/translational/post-translational regulation, metabolic physiology, disease associations, and therapeutic inhibition.
  • Includes a table of confirmed non-neuronal BACE1 substrates and their experimental evidence, plus figures on BACE1 structure, isoforms, post-translational modifications, insulin/leptin pathways, BAT commitment, and vasculature.
  • Discusses preclinical models (BACE1 knockout/knock-in, diet-induced obese mice, cell culture, zebrafish) and clinical trial data for BACE1 inhibitors including Verubecestat and Lanabecestat.

Limitations

  • The authors state that the mechanisms linking BACE1 to leptin resistance are unclear, that BACE1-mediated proteolysis of the leptin receptor is yet to be determined, and that many areas require further investigation.
  • The authors note contradictory findings, including that both Aβ and BACE1 inhibitors can inhibit angiogenesis in tumor models, and that plasma Aβ lacks consensus as an AD biomarker.
  • Evident from the text: this is a narrative review without a stated systematic search strategy, and many conclusions rely on preclinical models or associative human data; the authors also note that identified BACE1 substrates are primarily neurological, possibly reflecting experimental design rather than true biological distribution.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/obr.13430

Cites

194 of 194 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

6 of 154 cited sources checked · 2 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Substrates SEZ6, L1CAM, LRRN1, neurotrimin, and CHL1 are involved in neurite outgrowth.

    “Substrates SEZ6, L1CAM, leucine rich repeat neuronal 1 (LRRN1), neurotrimin, and CHL1 are all involved in neurite outgrowth.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Kuhn PH, Koroniak K, Hogl S, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012; 31(14): 3157‐ 3168. 22728825 PMC3400020 source
  • Premisecitation

    Nearly 70 BACE1 substrates have been identified to date.

    “through secretome enrichment experiments, nearly 70 BACE1 substrates have been identified to date.”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [22] Njavro JR, Klotz J, Dislich B, et al. Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1. FASEB K. 2020; 34(2): 2465‐ 2482. 31908000 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [23] Kuhn PH, Koroniak K, Hogl S, et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 2012; 31(14): 3157‐ 3168. 22728825 PMC3400020 source

      The paper’s Abstract reports that secretome protein enrichment with click sugars (SPECS) identified 34 BACE1 substrates in primary neurons. This supports the identification method, but the paper does not substantiate the claim that nearly 70 substrates had been identified through secretome enrichment experiments to date. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Pigoni M, Wanngren J, Kuhn PH, et al. Seizure protein 6 and its homolog seizure 6‐like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener. 2016; 11(1): 67. 27716410 PMC5053352 source

      The Background and Discussion report that proteomic studies identified more than 40 potential BACE1 substrates, supporting the general point that many candidates had been found. They do not give a figure of nearly 70, and they say only a few candidates had been validated. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] Lichtenthaler SF, Dominguez DI, Westmeyer GG, et al. The cell adhesion protein P‐selectin glycoprotein ligand‐1 is a substrate for the aspartyl protease BACE1. J Biol Chem. 2003; 278(49): 48713‐ 48719. 14507929 source
  • Premisecitation

    In order for the mature BACE1 protein to be produced, glycosylation and transient acetylation in the ER are required.

    “In order for the mature BACE1 protein to be produced, glycosylation and transient acetylation in the ER are required.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [73] Costantini C, Ko MH, Jonas MC, Puglielli L. A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1. Biochem J. 2007; 407(3): 383‐ 395. 17425515 PMC2275071 source
  • Premisecitation

    Through additional substrates, BACE1 has been implicated in inflammation, cardiovascular function, glucose homeostasis, and insulin signaling.

    “Through these additional substrates, BACE1 has been implicated in inflammation, cardiovascular function, glucose homeostasis, and insulin signaling”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [18] Meakin PJ, Mezzapesa A, Benabou E, et al. The beta secretase BACE1 regulates the expression of insulin receptor in the liver. Nat Commun. 2018; 9: 14. 29610518 PMC5880807 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [34] Plucińska K, Dekeryte R, Koss D, et al. Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia. 2016; 59(7): 1513‐ 1523. 27138913 PMC4901117 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [35] Moore KJ, El Khoury J, Medeiros LA, et al. A CD36‐initiated signaling cascade mediates inflammatory effects of beta‐amyloid. J Biol Chem. 2002; 277(49): 47373‐ 47379. 12239221 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [36] Carrano A, Hoozemans JJM, van der Vies SM, Rozemuller AJM, van Horssen J, de Vries HE. Amyloid beta induces oxidative stress‐mediated blood‐brain barrier changes in capillary amyloid angiopathy. Antioxid Redox Signal. 2011; 15(5): 1167‐ 1178. 21294650 source
    • cites [37] Iadecola C, Zhang FY, Niwa K, et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nat Neurosci. 1999; 2(2): 157‐ 161. 10195200 source
    • cites [38] Greco S, Zaccagnini G, Fuschi P, et al. Increased BACE1‐AS long noncoding RNA and β‐amyloid levels in heart failure. Cardiovasc Res. 2017; 113(5): 453‐ 463. 28158647 source
  • Premisecitation

    Some observed phenotypes, such as impaired axon guidance, are more severe when BACE1 is deficient in the developmental stages.

    “Some of the observed phenotypes, such as impaired axon guidance, are more severe when BACE1 is deficient in the developmental stages.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Ou‐Yang MH, Kurz JE, Nomura T, et al. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med. 2018; 10(459): eaao5620. 30232227 PMC11017370 source
  • It may state two separate claims as one. 61
  • Probably not a substantial claim. 10

  • It may state two separate claims as one.

    Premisecitation

    NSAIDs lower BACE1 activity, likely by reducing PPARγ levels.

    “Additionally, studies showed that NSAIDs, used to decrease inflammation, lower BACE1 activity, likely by reducing PPARy levels.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [53] Sastre M, Dewachter I, Rossner S, et al. Nonsteroidal anti‐inflammatory drugs repress ‐secretase gene promoter activity by the activation of PPAR. Proc Natl Acad Sci. 2006; 103(2): 443‐ 448. 16407166 PMC1326151 source

      The paper supports the claim that certain NSAIDs reduce BACE1 promoter activity, but it says they do so through PPARγ activation, not by reducing PPARγ levels. The Abstract states that NSAIDs suppress the decrease in PPARγ transcription caused by inflammatory cytokines; the Results report that ibuprofen, indomethacin, and naproxen repressed BACE1 promoter activity. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [54] Rossner S, Sastre M, Bourne K, Lichtenthaler SF. Transcriptional and translational regulation of BACE1 expression—implications for Alzheimer's disease. Prog Neurobiol. 2006; 79(2): 95‐ 111. 16904810

  • It may state two separate claims as one.

    Premisecitation

    Insulin and Aβ have a similar tertiary structure and both bind to IR, making Aβ a competitive inhibitor able to reduce cellular insulin sensitivity.

    “Insulin and Aβ have a similar tertiary structure and both bind to IR, making Aβ a competitive inhibitor able to reduce cellular insulin sensitivity”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [93] Wang X, Yu S, Gao SJ, Hu JP, Wang Y, Liu HX. Insulin inhibits Abeta production through modulation of APP processing in a cellular model of Alzheimer's disease. Neuro Endocrinol Lett. 2014; 35(3): 224‐ 229. 24977973

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [94] Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer's beta‐amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci. 2002; 22(10): Rc221. 12006603 PMC6757630 source

      The Discussion reports that Aβ competes with insulin for receptor binding and inhibits insulin-promoted receptor autophosphorylation in vitro. It describes a shared sequence motif, not a demonstrated similarity in tertiary structure. Reduced cellular insulin sensitivity is a possible consequence, not a cellular effect established by these experiments. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    L1CAM and CHL1 are BACE1 substrates involved in axon guidance.

    “L1 cell adhesion molecule (L1CAM) and neural cell adhesion molecule L1‐like protein (CHL1) are BACE1 substrates involved in axon guidance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Zhou LJ, Barao S, Laga M, et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J Biol Chem. 2012; 287(31): 25927‐ 25940. 22692213 PMC3406677 source

  • It may state two separate claims as one.

    Premisecitation

    PSGL-1 is a BACE1 substrate that plays an important role in immune defenses by recruiting white blood cells to the site of infection.

    “P‐selectin glycoprotein ligand‐1 (PSGL‐1) is a BACE1 substrate that plays an important role in immune defenses by recruiting white blood cells to the site of infection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Lichtenthaler SF, Dominguez DI, Westmeyer GG, et al. The cell adhesion protein P‐selectin glycoprotein ligand‐1 is a substrate for the aspartyl protease BACE1. J Biol Chem. 2003; 278(49): 48713‐ 48719. 14507929 source

  • It may state two separate claims as one.

    Premisecitation

    In a variety of pathological conditions, including AD, cerebral amyloid angiopathy, and metabolic diseases such as type 2 diabetes and obesity, BACE1 expression and activity are increased and drive disease progression.

    “In a variety of pathological conditions, including AD, cerebral amyloid angiopathy, and metabolic diseases such as type 2 diabetes and obesity, BACE1 expression and activity are increased and drive disease progression.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Vassar R. Beta‐secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286(5440): 735‐ 741. 10531052
    • cites [34] Plucińska K, Dekeryte R, Koss D, et al. Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia. 2016; 59(7): 1513‐ 1523. 27138913 PMC4901117 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [39] Niwa K, Carlson GA, Iadecola C. Exogenous A beta1‐40 reproduces cerebrovascular alterations resulting from amyloid precursor protein overexpression in mice. J Cereb Blood Flow Metab. 2000; 20(12): 1659‐ 1668. 11129782 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [40] Alonzo NC, Hyman BT, Rebeck GW, Greenberg SM. Progression of cerebral amyloid angiopathy: accumulation of amyloid‐beta40 in affected vessels. J Neuropathol Exp Neurol. 1998; 57(4): 353‐ 359. 9600229 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given

    To date, the BACE1 substrates identified are primarily associated with neurological function and the central nervous system.

    “To date, the BACE1 substrates identified are primarily associated with neurological function and the central nervous system.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    BACE1 knockout mice models exhibit reduced weight gain, increased energy expenditure, and enhanced leptin signaling.

    “The phenotype of the BACE1 knockout mice models, including reduced weight gain, increased energy expenditure, and enhanced leptin signaling, proposes a physiological role of BACE1 in regulating energy metabolism and homeostasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Wang H, Li R, Shen Y. β‐Secretase: its biology as a therapeutic target in diseases. Trends Pharmacol Sci. 2013; 34(4): 215‐ 225. 23452816 PMC3691103 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    BACE1 knockout mice display reduced birth weight, hypomyelination, memory deficits, behavioral alterations, axon guidance impairment, impaired midbrain dopaminergic signaling, seizures, and abnormal electroencephalograms.

    “Conversely, BACE1 knockout mice display reduced birth weight, hypomyelination, memory deficits, behavioral alterations, axon guidance impairment, impaired midbrain dopaminergic signaling, seizures, and abnormal electroencephalograms (EEGs).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Hu X, He W, Diaconu C, et al. Genetic deletion of BACE1 in mice affects remyelination of sciatic nerves. FASEB K. 2008; 22(8): 2970‐ 2980. PMC2493455 18413858 source
    • cites [43] Ou‐Yang MH, Kurz JE, Nomura T, et al. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci Transl Med. 2018; 10(459): eaao5620. 30232227 PMC11017370 source

  • It may state two separate claims as one.

    Premisecitation

    SEZ6 and SEZ6L proteins influence ER functions in neurons, control synaptic connectivity, and motor coordination and may be responsible for the seizures, motor deficits, and reduced spinal deficiency observed in BACE1 null mice.

    “Seizure protein 6 (SEZ6) and seizure‐like protein 6 (SEZ6L) proteins influence ER functions in neurons, control synaptic connectivity, and motor coordination and therefore may likely be responsible for the seizures, motor deficits, and reduced spinal deficiency observed in BACE1 null mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Pigoni M, Wanngren J, Kuhn PH, et al. Seizure protein 6 and its homolog seizure 6‐like protein are physiological substrates of BACE1 in neurons. Mol Neurodegener. 2016; 11(1): 67. 27716410 PMC5053352 source

  • It may state two separate claims as one.

    Premisecitation

    Recent studies implicate BACE1 in alterations in insulin and leptin signaling, presenting BACE1 action as a potential link between AD and T2D.

    “Recent studies implicate BACE1 in alterations in insulin and leptin signaling, presenting BACE1 action as a potential link between AD and T2D.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009; 1792(5): 482‐ 496. 19026743 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    In addition to insulin signaling, other metabolic changes associated with BACE1 have been observed, including lowered plasma leptin and restored hypothalamic leptin sensitivity in obese mice.

    “In addition to insulin signaling, other metabolic changes associated with BACE1 have been observed, including lowered plasma leptin and restored hypothalamic leptin sensitivity in obese mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Meakin PJ, Jalicy SM, Montagut G, et al. Bace1‐dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Sci Rep. 2018; 8(1): 1‐ 16. 29311632 PMC5758523 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    The action of BACE1-AS has been implicated in AD pathology, with increased BACE-AS in turn increasing BACE1 and Aβ-42.

    “The action of BACE1‐AS has been implicated in AD pathology, with increased BACE‐AS in turn increasing BACE1 and Aβ‐42.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Li F, Wang Y, Yang H, et al. The effect of BACE1‐AS on β‐amyloid generation by regulating BACE1 mRNA expression. BMC Mol Biol. 2019; 20(1): 23. 31570097 PMC6771094 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    Glycosylation has been implicated in the pathological increases in BACE1 stability seen in response to oxidative stress, with bisecting N-acetylglucosamine (GlcNAc) having been shown to prevent lysosomal degradation of BACE1.

    “Glycosylation has also been implicated in the pathological increases in BACE1 stability seen in response to oxidative stress, with bisecting N‐acetylglucosamine (GlcNAc), catalyzed by GlcNAc transferase Gnt‐III having been shown to prevent lysosomal degradation of BACE1.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Kizuka Y, Kitazume S, Fujinawa R, et al. An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease. EMBO Mol Med. 2015; 7(2): 175‐ 189. 25592972 PMC4328647 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [77] Kizuka Y, Nakano M, Kitazume S, Saito T, Saido TC, Taniguchi N. Bisecting GlcNAc modification stabilizes BACE1 protein under oxidative stress conditions. Biochem J. 2016; 473(1): 21‐ 30. 26467158 source

  • It may state two separate claims as one.

    Premisecitation

    Overexpression of BACE1 decreases CREB phosphorylation, in turn decreasing protein kinase A activity and cyclic adenosine monophosphate levels.

    “Overexpression of BACE1 has been shown to decrease CREB phosphorylation, in turn decreasing protein kinase A (PKA) activity, and cyclic adenosine monophosphate (cAMP) levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Chen Y, Huang X, Zhang YW, et al. Alzheimer's ‐secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of ‐amyloid. J Neurosci. 2012; 32(33): 11390‐ 11395. 22895721 PMC3446780 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    This may have important implications in the context of T2D and obesity, as well as providing a potential mechanistic explanation for the increased risk of AD in T2D patients.

    “This may have important implications in the context of T2D and obesity, as well as providing a potential mechanistic explanation for the increased risk of AD in T2D patients.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The released soluble insulin receptor (IRsol) is able to bind insulin, reducing the abundance of bioavailable insulin, and further impairing insulin signaling.

    “The released soluble IR (IRsol) is able to bind insulin, reducing the abundance of bioavailable insulin, and further impairing insulin signaling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    There are six relatively established BACE1 isoforms (A-F), in addition to reports of various less well-characterized forms including BACE1-455 and BACE1-127.

    “There are six relatively established BACE1 isoforms (A–F), in addition to reports of various less well‐characterized forms including BACE1‐455 and BACE1‐127”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [66] Tanahashi H, Tabira T. Three novel alternatively spliced isoforms of the human beta‐site amyloid precursor protein cleaving enzyme (BACE) and their effect on amyloid beta‐peptide production. Neurosci Lett. 2001; 307(1): 9‐ 12. 11516562 source
    • cites [67] Ehehalt R, Michel B, De Pietri Tonelli D, Zacchetti D, Simons K, Keller P. Splice variants of the beta‐site APP‐cleaving enzyme BACE1 in human brain and pancreas. Biochem Biophys Res Commun. 2002; 293(1): 30‐ 37. 12054559 source
    • cites [68] Mowrer KR, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid beta‐peptide production. J Biol Chem. 2008; 283(27): 18694‐ 18701. 18468996 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [69] Tanahashi H, Tabira T. A novel beta‐site amyloid precursor protein cleaving enzyme (BACE) isoform regulated by nonsense‐mediated mRNA decay and proteasome‐dependent degradation. Neurosci Lett. 2007; 428(2–3): 103‐ 108. 17961921 source

  • It may state two separate claims as one.

    Premisecitation

    The BACE1 protein is acetylated at seven different lysine residues mediated by CoA:lysine acetyltransferase 1 and 2, and ubiquitinated at K501 which causes translocation to the lysosomes for degradation.

    “The BACE1 protein is also acetylated at seven different lysine residues mediated by CoA:lysine acetyltransferase 1 and 2 (ATase 1 and ATase 2), and ubiquitinated at K501 which causes translocation to the lysosomes for degradation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Wang H, Li R, Shen Y. β‐Secretase: its biology as a therapeutic target in diseases. Trends Pharmacol Sci. 2013; 34(4): 215‐ 225. 23452816 PMC3691103 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    BACE1 inhibition can restore insulin signaling in the setting of palmitate-induced inflammation and ER stress, while mimicked by sAPPβ.

    “BACE1 inhibition can restore insulin signaling in this setting, while mimicked by sAPPβ.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Botteri G, Salvadó L, Gumà A, et al. The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling. Metabolism. 2018; 85: 59‐ 75. 29526536 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationcitation

    Dysregulation of PTMs has a substantial impact on BACE1, either altering enzyme activity or cellular localization, and may play an important role in alterations in BACE1 activity in response to physiological stimuli.

    “Dysregulation of PTMs therefore has a substantial impact on BACE1, either altering enzyme activity or cellular localization, and may play an important role in alterations in BACE1 activity in response to physiological stimuli.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Araki W. Post‐translational regulation of the β‐secretase BACE1. Brain Res Bull. 2016; 126(Pt 2): 170‐ 177. 27086128

  • It may state two separate claims as one.

    Premisecitation

    BACE1 activity is regulated at the transcriptional, post-transcriptional, and translation level, with post-translational modifications required to produce the mature BACE1 protein.

    “BACE1 activity is regulated at the transcriptional, post‐transcriptional, and translation level, with post‐translational modifications (PTMs) required to produce the mature BACE1 protein.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Araki W. Post‐translational regulation of the β‐secretase BACE1. Brain Res Bull. 2016; 126(Pt 2): 170‐ 177. 27086128

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Generally, a greater fat deposit in adipocytes results in greater leptin release, and therefore, theoretically, increased lipids should equate to decreased hunger.

    “Generally, a greater fat deposit in adipocytes results in greater leptin release, and therefore, theoretically, increased lipids should equate to decreased hunger.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [104] Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med. 2013; 7(2): 207‐ 222. 23580174 PMC4069066 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [105] Ahima RS. Revisiting leptin's role in obesity and weight loss. J Clin Invest. 2008; 118(7): 2380‐ 2383. 18568083 PMC2430504
    • cites [106] Frederich RC, Hamann A, Anderson S, Löllmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet‐induced resistance to leptin action. Nat Med. 1995; 1(12): 1311‐ 1314. 7489415 source

  • It may state two separate claims as one.

    Premisecitation

    BACE1 is phosphorylated, with phosphorylation at threonine 252 via p25/Cdk5 pathways found to stimulate protease activity.

    “BACE1 is also phosphorylated, with phosphorylation at threonine 252 via p25/Cdk5 pathways found to stimulate protease activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Song WJ, Son MY, Lee HW, Seo H, Kim JH, Chung SH. Enhancement of BACE1 activity by p25/Cdk5‐mediated phosphorylation in Alzheimer's disease. PLoS ONE. 2015; 10(8): 16. PMC4552876 26317805 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Interpretationcitation

    The presence of a CREB binding site within the BACE1 promoter suggests that BACE1 regulation of the cAMP/PKA/CREB pathway may feedback to regulation of BACE1 gene expression.

    “Although not well characterized, the presence of a CREB binding site within the BACE1 promoter suggests that BACE1 regulation of the cAMP/PKA/CREB pathway, significant in glucose metabolism and lipid homeostasis, may feedback to regulation of BACE1 gene expression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Lahiri DK, Ge YW, Rogers JT, Sambamurti K, Greig NH, Maloney B. Taking down the unindicted co‐conspirators of amyloid beta‐peptide‐mediated neuronal death: shared gene regulation of BACE1 and APP genes interacting with CREB, Fe65 and YY1 transcription factors. Curr Alzheimer Res. 2006; 3(5): 475‐ 483. 17168646 source

  • It may state two separate claims as one.

    Premisecitation

    APP, BACE1, and BACE2 are all expressed in the liver, and a 30% increase in circulating Aβ was observed when APP expression was restricted to hepatocytes in a mouse model.

    “APP, BACE1, and BACE2 are all expressed in the liver, and a 30% increase in circulating Aβ was observed when APP expression was restricted to hepatocytes in a mouse model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Lam V, Takechi R, Hackett MJ, et al. Synthesis of human amyloid restricted to liver results in an Alzheimer disease‐like neurodegenerative phenotype. PLoS Biol. 2021; 19(9): e3001358. 34520451 PMC8439475 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    JAK/STAT3 signaling is also regulated by leptin, providing a link to other aspects of the metabolic syndrome.

    “Notably, JAK/STAT3 signaling is also regulated by leptin, providing a link to other aspects of the metabolic syndrome.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Gurzov EN, Stanley WJ, Pappas EG, Thomas HE, Gough DJ. The JAK/STAT pathway in obesity and diabetes. FEBS j. 2016; 283(16): 3002‐ 3015. 26972840 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Metabolic dysfunction and type 2 diabetes mellitus are long established risk factors for AD, with T2D sufferers having a 50% increased risk of developing AD.

    “Metabolic dysfunction and type 2 diabetes mellitus (T2D) are long established risk factors for AD, with T2D sufferers having a 50% increased risk of developing AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] WHO. Diabetes. https://www.who.int/news-room/fact-sheets/detail/diabetes. Published 2020. Accessed 24th February 2021.

  • It may state two separate claims as one.

    Premisecitation

    Therapeutic inhibition of BACE2 in mice has been linked to increased pancreatic β-cell function and mass, enhanced insulin production and improved glucose homeostasis, likely via its role in the cleavage of Tmem27.

    “Furthermore, therapeutic inhibition of BACE2 in mice, has been linked to increased pancreatic β‐cell function and mass, enhanced insulin production and improved glucose homeostasis, likely via its role in the cleavage of Tmem27.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Esterházy D, Stützer I, Wang H, et al. Bace2 is a β cell‐enriched protease that regulates pancreatic β cell function and mass. Cell Metab. 2011; 14(3): 365‐ 377. 21907142 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 plays a pivotal role in effective insulin signaling, with high levels of BACE1 leading to reduced insulin signaling and glucose uptake, and vice versa.

    “BACE1 plays a pivotal role in effective insulin signaling, with high levels of BACE1 leading to reduced insulin signaling and glucose uptake, and vice versa.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The BACE1 protein has four N-linked glycosylation sites, which are targeted in the Golgi and facilitate pro-peptide processing, maturation, and transportation.

    “The BACE1 protein has four N‐linked glycosylation sites, which are targeted in the Golgi and facilitate pro‐peptide processing, maturation, and transportation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Cole SL, Vassar R. The basic biology of BACE1: a key therapeutic target for Alzheimer's disease. Curr Genomics. 2007; 8(8): 509‐ 530. 19415126 PMC2647160

  • It may state two separate claims as one.

    Premisecitation

    The ubiquitination site at 501 is also competitively SUMOylated, which stabilizes the protein and promotes its activity.

    “The ubiquitination site at 501 is also competitively SUMOylated, which stabilizes the protein and promotes its activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Bao J, Qin M, Mahaman YAR, et al. BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer's disease. Proc Natl Acad Sci USA. 2018; 115(15): 3954‐ 3959. 29581300 PMC5899489 source

  • It may state two separate claims as one.

    Premisecitation

    Tissue expression of BACE1 and plasma levels of the IRsol are higher in patients with T2D, supporting the theory that BACE1 cleavage of IR drives the disease.

    “Tissue expression of BACE1 and plasma levels of the IRsol are higher in patients with T2D, supporting the theory that BACE1 cleavage of IR drives the disease.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Meakin PJ, Harper AJ, Hamilton DL, et al. Reduction in BACE1 decreases body weight, protects against diet‐induced obesity and enhances insulin sensitivity in mice. Biochem J. 2012; 441: 285‐ 296. 21880018 PMC3242510 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [87] Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes. 2007; 56(8): 2028‐ 2035. 17563065

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationreasoning

    This suggests that alternative splicing may be an important mechanism of regulation of BACE1 activity and may underlie cleavage of different substrates and tissue-specific effects.

    “This suggests that alternative splicing may be an important mechanism of regulation of BACE1 activity and may underlie cleavage of different substrates and tissue‐specific effects; however, this requires further investigation.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Isoform A is 501 amino acids long and is reported to have superior protease activity.

    “Isoform A is 501 amino acids long and is reported to have superior protease activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Mowrer KR, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid beta‐peptide production. J Biol Chem. 2008; 283(27): 18694‐ 18701. 18468996 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    A greater number of individuals observed a weight loss of at least 7% when taking Lanabecestat than placebo, with mean weight loss at −1.9 kg for 50-mg Lanabecestat group compared with 0 for placebo.

    “A greater number of individuals observed a weight loss of at least 7% when taking Lanabecestat, than individuals taking the placebo, with mean weight loss at −1.9 kg for the 50‐mg Lanabecestat group compared with 0 for the placebo group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Wessels AM, Tariot PN, Zimmer JA, et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK‐ALZ randomized clinical trials. JAMA Neurol. 2020; 77(2): 199‐ 209. 31764959 PMC6902191 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 has a role in leptin sensitivity and is responsible for energy expenditure and thermogenesis, and the homologous BACE2 enzyme may also play an alternative role.

    “This presents a role for the BACE1 in leptin sensitivity and responsible for energy expenditure and thermogenesis and suggests that the homologous BACE2 enzyme may also play an alternative role.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    The BACE1 promotor has an NFκB binding site; when phosphorylated, NFκB increases BACE1 promotor activity and transcription.

    “The BACE1 promotor has an NFκB binding site. When phosphorylated, NFκB increases BACE1 promotor activity and transcription.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Chen CH, Zhou W, Liu S, et al. Increased NF‐κB signalling up‐regulates BACE1 expression and its therapeutic potential in Alzheimer's disease. Int J Neuropsychopharmacol. 2012; 15(1): 77‐ 90. 21329555 source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationreasoning

    Repurposing of BACE1 inhibitory drugs for treatment of metabolic syndromes such as diabetes and obesity, or as a dual therapy against both diseases, could be a huge advancement in the treatment of metabolic disorders.

    “Given the extent of research into effective BACE1 inhibitors for AD, the repurposing of BACE1 inhibitory drugs for treatment of metabolic syndromes such as diabetes and obesity, or as a dual therapy against both diseases, could be a huge advancement in the treatment of metabolic disorders.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Findings from mouse models of BACE1 manipulation translate to human metabolic physiology and disease.

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 has an important metabolic role and is a potential therapeutic target for the treatment of obesity induced diabetes.

    “This presents an important metabolic role for BACE1 and highlights BACE1 as a potential therapeutic target for the treatment of obesity induced diabetes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from mouse models of BACE1 manipulation translate to human metabolic physiology and disease.

  • It may state two separate claims as one.

    Interpretationreasoning

    ST6Gal-1 is found at decreased levels in atherosclerosis development, suggesting a role for BACE1 in its regulation.

    “ST6Gal‐1 is found at decreased levels in atherosclerosis development, this suggests a role for BACE1 in its regulation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    BACE1 has been implicated in body weight regulation via thermogenesis and its role in BAT differentiation.

    “In addition to β‐oxidation via leptin signaling, BACE1 has also been implicated in body weight regulation via thermogenesis and its role in BAT differentiation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Oliverio M, Schmidt E, Mauer J, et al. Dicer1‐miR‐328‐Bace1 signalling controls brown adipose tissue differentiation and function. Nat Cell Biol. 2016; 18(3): 328‐ 336. 26900752 source

  • It may state two separate claims as one.

    Premisecitation

    In vivo silencing of BACE1 was found to delay DIO induced weight gain, improve glucose tolerance, increase energy expenditure and insulin sensitivity, and elevate UCP1 expression in brown fat.

    “Furthermore, in vivo silencing of BACE1 was found to delay DIO induced weight gain, improve glucose tolerance, increase energy expenditure and insulin sensitivity, and elevate UCP1 expression in brown fat.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Meakin PJ, Harper AJ, Hamilton DL, et al. Reduction in BACE1 decreases body weight, protects against diet‐induced obesity and enhances insulin sensitivity in mice. Biochem J. 2012; 441: 285‐ 296. 21880018 PMC3242510 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    BACE2 knockout is associated with an adverse metabolic phenotype, including enhanced weight gain, hyperphagia, hyperinsulinemia, and leptin and insulin resistance.

    “By contrast, BACE2 knockout is associated with an adverse metabolic phenotype, including enhanced weight gain, hyperphagia, hyperinsulinemia, and leptin and insulin resistance.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Díaz‐Catalán D, Alcarraz‐Vizán G, Castaño C, et al. BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet. Mol Metab. 2021; 53: 101251. 34015524 PMC8190493 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    Verubecestat adverse side effects included increase in falls and injuries, sleep disturbance, suicidal thoughts, hair color change and weight loss along with decreased appetite.

    “Adverse side effects were seen including an increase in falls and injuries, sleep disturbance, suicidal thoughts, hair color change and weight loss along with decreased appetite.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Egan MF, Mukai Y, Voss T, et al. Further analyses of the safety of verubecestat in the phase 3 EPOCH trial of mild‐to‐moderate Alzheimer's disease. Alzheimers Res Ther. 2019; 11(1): 68. 31387606 PMC6685277

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    These effects likely occur through the action of BACE1 on the leptin pathway and insulin signaling pathway.

    “These effects likely occur through the action of BACE1 on the leptin pathway and insulin signaling pathway, and could revolutionize the treatment of metabolic dysfunction.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    Metabolic drugs including statins and metformin downregulate BACE1, and it is possible the desired action of these drugs occurs via their impact on BACE1 expression.

    “Metabolic drugs are known to downregulate BACE1, including statins and metformin, and although it requires further investigation, it is possible the desired action of these drugs occurs via their impact on BACE1 expression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    There is an inverse relationship between BACE1 and leptin signaling: BACE1 expression is suppressed by leptin signaling, whereas BACE1 levels are increased by both obesity and T2D.

    “There is evidence of an inverse relationship between BACE1 and leptin signaling. BACE1 expression is suppressed by leptin signaling, whereas BACE1 levels are increased by both obesity and T2D.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Marwarha G, Raza S, Meiers C, Ghribi O. Leptin attenuates BACE1 expression and amyloid‐β genesis via the activation of SIRT1 signaling pathway. Biochim Biophys Acta. 2014; 1842(9): 1587‐ 1595. 24874077 PMC4125440 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    Both BACE1 knockout and inhibitor-treated mice show no change in daily food intake while presenting with decreased body weight.

    “Interestingly, both BACE1 knockout and inhibitor‐treated mice show no change in daily food intake while presenting with decreased body weight”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Meakin PJ, Harper AJ, Hamilton DL, et al. Reduction in BACE1 decreases body weight, protects against diet‐induced obesity and enhances insulin sensitivity in mice. Biochem J. 2012; 441: 285‐ 296. 21880018 PMC3242510 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [19] Meakin PJ, Jalicy SM, Montagut G, et al. Bace1‐dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Sci Rep. 2018; 8(1): 1‐ 16. 29311632 PMC5758523 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    The BACE1-AS/BACE1/Aβ axis has important physiological functions outside the brain.

    “It is clear that the BACE1‐AS/BACE1/Aβ axis has important physiological functions outside the brain.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    BACE1 regulates Notch3 signaling via direct cleavage of JAG1, in turn, increasing aberrant angiogenesis and vessel sprouting.

    “BACE1 regulates Notch3 signaling via direct cleavage of JAG1, in turn, increasing aberrant angiogenesis and vessel sprouting.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] He W, Hu J, Xia Y, Yan R. β‐site amyloid precursor protein cleaving enzyme 1(BACE1) regulates Notch signaling by controlling the cleavage of Jagged 1 (Jag1) and Jagged 2 (Jag2) proteins. J Biol Chem. 2014; 289(30): 20630‐ 20637. 24907271 PMC4110275 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    Lanabecestat could treat excess weight observed in obesity, without causing extreme weight loss when BMI is reduced.

    “suggesting Lanabecestat could treat excess weight observed in obesity, without causing extreme weight loss when BMI is reduced.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Statins are associated with decreased Aβ formation, attributed to the reduction in cholesterol which in turn regulates BACE1.

    “Statins are associated with decreased Aβ formation, attributed to the reduction in cholesterol which in turn regulates BACE1.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [180] Zhang X, Wen J, Zhang Z. Statins use and risk of dementia: a dose‐response meta analysis. Medicine (Baltimore). 2018; 97(30): e11304. 30045255 PMC6078755 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [181] Sparks DL, Sabbagh MN, Connor DJ, et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol. 2005; 62(5): 753‐ 757. 15883262 source
    • cites [182] Sparks DL, Kryscio RJ, Sabbagh MN, Connor DJ, Sparks LM, Liebsack C. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res. 2008; 5(4): 416‐ 421. 18690839 source

  • It may state two separate claims as one.

    Premisecitation

    Several BACE1 inhibitory drugs have been developed, yet despite progression to phase 3 clinical trials, none have made it to wide clinical use.

    “Several BACE1 inhibitory drugs have been developed, yet despite progression to phase 3 clinical trials, none have made it to wide clinical use.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Moussa‐Pacha NM, Abdin SM, Omar HA, Alniss H, Al‐Tel TH. BACE1 inhibitors: current status and future directions in treating Alzheimer's disease. Med Res Rev. 2020; 40(1): 339‐ 384. 31347728 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Obesity induced Dicer1 downregulation decreases miR-328, preventing BACE1 silencing and causing a decrease in BAT differentiation and thermogenesis as well as BACE1-mediated impairments in glucose metabolism and homeostasis.

    “This suggests that obesity induced Dicer1 downregulation decreases miR‐328, preventing BACE1 silencing and causing a decrease in BAT differentiation and thermogenesis as well as BACE1‐mediated impairments in glucose metabolism and homeostasis.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Verubecestat showed a reduction in cerebrospinal fluid Aβ levels to 63%-81%, but no beneficial effect on cognition was observed.

    “Despite showing a reduction in cerebrospinal fluid Aβ levels to 63%–81%, no beneficial effect on cognition was observed for Verubecestat.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild‐to‐moderate Alzheimer's disease. N Engl J Med. 2018; 378(18): 1691‐ 1703. 29719179 PMC6776074

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    BACE1 protein is detectable in plasma and levels are significantly raised in patients with mild cognitive impairment, while also predicting conversion of MCI to AD.

    “BACE1 protein is detectable in plasma and levels are significantly raised in patients with mild cognitive impairment, while also predicting conversion of MCI to AD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Shen Y, Wang H, Sun Q, et al. Increased plasma beta‐secretase 1 may predict conversion to Alzheimer's disease dementia in individuals with mild cognitive impairment. Biol Psychiatry. 2018; 83(5): 447‐ 455. 28359566 PMC5656540 source

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 regulates immune cell function; however, this may be disease and/or stimulus dependent.

    “Collectively, this points to BACE1 regulating immune cell function; however, this may be disease and/or stimulus dependent and warrants further investigation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 has an important physiological role within the cardiovascular system and is an important enzyme in cardiovascular disease.

    “Together, this presents an important physiological role for BACE1 within the cardiovascular system and as an important enzyme in cardiovascular disease.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Dysregulation of the BACE1/BACE1-AS/Aβ axis is associated with heart failure, with both BACE1-AS and BACE1 found upregulated.

    “Furthermore, the dysregulation of the BACE1/BACE1‐AS/Aβ axis is associated with heart failure, with both BACE1‐AS and BACE1 found upregulated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Greco S, Zaccagnini G, Fuschi P, et al. Increased BACE1‐AS long noncoding RNA and β‐amyloid levels in heart failure. Cardiovasc Res. 2017; 113(5): 453‐ 463. 28158647 source

  • It may state two separate claims as one.

    Interpretationreasoning

    BACE1 is a pivotal enzyme in the development of cellular leptin resistance observed in obesity and T2D; however, the mechanism is unclear.

    “Taken together, this suggests BACE1 is a pivotal enzyme in the development of cellular leptin resistance observed in obesity and T2D; however, the mechanism is unclear.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Plasma BACE1 protein levels are elevated in people with T2D and correlate with glycemic control, independently of cognition.

    “Furthermore, plasma BACE1 protein levels are elevated in people with T2D and correlate with glycemic control, independently of cognition.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Bao H, Liu Y, Zhang M, et al. Increased β‐site APP cleaving enzyme 1‐mediated insulin receptor cleavage in type 2 diabetes mellitus with cognitive impairment. Alzheimers Dement. 2021; 17(7): 1097‐ 1108. 33410588 source

  • It may state two separate claims as one.

    Premisecitation

    Inhibition of BACE1 in DIO mice normalized the STAT3 response, alongside improving glucose homeostasis, reducing hypothalamic inflammation, and normalizing hypothalamic leptin sensitivity via NPY, AgRP, and POMC signaling.

    “Inhibition of BACE1 in diet‐induced obese (DIO) mice normalized the STAT3 response, alongside improving glucose homeostasis, reducing hypothalamic inflammation, and normalizing hypothalamic leptin sensitivity via NPY, AgRP, and POMC signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Meakin PJ, Jalicy SM, Montagut G, et al. Bace1‐dependent amyloid processing regulates hypothalamic leptin sensitivity in obese mice. Sci Rep. 2018; 8(1): 1‐ 16. 29311632 PMC5758523 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    Inflammation induced activation of NFκB facilitates upregulation of BACE1 expression, and subsequently increases Aβ production.

    “Thus, inflammation induced activation of NFκB, facilitates the upregulation of BACE1 expression, and subsequently increase Aβ production.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    BACE1 knock-in was found to increase adipogenesis, hyperleptinemia, PTP1B, and ER stress.

    “Supporting this, BACE1 knock‐in was found to increase adipogenesis, hyperleptinemia, PTP1B, and ER stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Plucińska K, Dekeryte R, Koss D, et al. Neuronal human BACE1 knockin induces systemic diabetes in mice. Diabetologia. 2016; 59(7): 1513‐ 1523. 27138913 PMC4901117 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    Metformin reduces neuronal insulin resistance and improves glucose uptake via activation of AMPK, IR, and PI3/Akt signaling, and attenuates production of Aβ.

    “The increasing evidence for insulin resistance and glucose metabolism playing an important role in dementia led to the investigation of metformin in AD treatment, where it was found to reduce neuronal insulin resistance and improve glucose uptake via activation of AMPK, IR, and PI3/Akt signaling, and attenuate production of Aβ.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175] Gupta A, Bisht B, Dey CS. Peripheral insulin‐sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's‐like changes. Neuropharmacology. 2011; 60(6): 910‐ 920. 21277873 source

  • It may state two separate claims as one.

    Premisecitation

    The lncRNA species BACE1-AS strongly correlates with BACE1 expression and is measurable in human plasma samples, with levels increased in patients with AD and autism.

    “The lncRNA species BACE1‐AS strongly correlates with BACE1 expression and is also measurable in human plasma samples, with levels increased in patients with AD 193 and autism.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [193] Wang D, Wang P, Bian X, et al. Elevated plasma levels of exosomal BACE1‐AS combined with the volume and thickness of the right entorhinal cortex may serve as a biomarker for the detection of Alzheimer's disease. Mol Med Rep. 2020; 22(1): 227‐ 238. 32377715 PMC7248487 source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [194] Ghafouri‐Fard S, Namvar A, Arsang‐Jang S, Komaki A, Taheri M. Expression analysis of BDNF, BACE1, and their natural occurring antisenses in autistic patients. J Mol Neurosci. 2020; 70(2): 194‐ 200. 31760580 source
66 of 66

  • The paper relies on this without support.

    Weight loss is observed with BACE1 inhibitors in clinical trials.

    “Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology.”

  • The paper relies on this without support.

    Obesity increases cdk5 and casein kinase 1 activity.

    “Furthermore obesity increases cdk5 and casein kinase 1 activity is enhanced.”

  • The paper relies on this without support.

    The weight loss observed with BACE1 inhibitors in clinical trials is due to BACE1 inhibition.

    “Taken together with the weight loss observed with BACE1 inhibitors in clinical trials, these data highlight a novel role for BACE1 in regulation of metabolic physiology.”

  • The paper relies on this without support.

    Findings from mouse models of BACE1 manipulation translate to human metabolic physiology and disease.

    “This presents an important metabolic role for BACE1 and highlights BACE1 as a potential therapeutic target for the treatment of obesity induced diabetes.”
4 of 4

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.

  • Interleukin-1 receptor II is labeled as receptor I in the table

    Minor

    The text identifies IL-1R2 as interleukin-1 receptor II, but Table 1 names it interleukin-1 receptor I.

  • Acetylation-site count differs from the figure

    Minor

    The text states that BACE1 is acetylated at seven lysine residues, while Figure 3 lists eight.

  • Insulin-signaling regulator has conflicting names

    Minor

    The text names PTP1B as a negative regulator of insulin signaling, whereas the Figure 4 caption names PTBP1 in the same role.

3 of 3

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1016/j.bbadis.2014.05.015

    Major

    The cited work was retracted on 2014-09-01 (notice 10.1016/j.bbadis.2014.05.015), before this paper was published (2022-02-04). Its authors could have known.

    Cited work 10.1016/j.bbadis.2014.05.015 · retracted 2014-09-01 · notice 10.1016/j.bbadis.2014.05.015 · this paper published 2022-02-04

  • Cites a retracted work: 10.1016/j.expneurol.2006.03.019

    Major

    The cited work was retracted on 2006-08-01 (notice 10.1016/j.expneurol.2006.03.019), before this paper was published (2022-02-04). Its authors could have known.

    Cited work 10.1016/j.expneurol.2006.03.019 · retracted 2006-08-01 · notice 10.1016/j.expneurol.2006.03.019 · this paper published 2022-02-04

2 of 2

Citations

Cites

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Related

Metadata

Authors
Taylor, H. A., Przemylska, L., Clavane, E. M., & Meakin, P. J.
Affiliations
  • University of Leeds (GB)
  • Discovery & Translational Science Department, Leeds Institute of Cardiovascular and Metabolic Medicine University of Leeds Leeds UK
Corresponding author
Meakin, Paul J.
ORCID
Venue
Obesity Reviews
Publisher
Wiley
Published
2022-02-04
Volume
23
Issue
7
Pages
e13430-e13430
ISSN
  • 1467-7881 (ISSN-L)
  • 1467-789X
DOI
10.1111/obr.13430
PMC
PMC9286785
OpenAlex
W4210406803
Cited by
107
References
194
Citations by year
2026: 20 · 2025: 25 · 2024: 32 · 2023: 22 · 2022: 7
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Obesity Reviews (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Funders
  • Biotechnology and Biological Sciences Research Council (BB/V014358/1)
  • British Heart Foundation (FS/18/38/33659, FS/4yPhD/F/20/34130)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
BACE1, beta-secretase, BACE1 inhibitors, energy metabolism, obesity, type 2 diabetes, cardiovascular disease, leptin signaling, metabolic disorders, Alzheimer's disease, amyloid-beta
MeSH terms
Animals, Diabetes Mellitus, Type 2, Humans, Obesity, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, 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.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

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 ›

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