BACE1: More than just a β‐secretase

In the paper

“Additionally, studies showed that NSAIDs, used to decrease inflammation, lower BACE1 activity, likely by reducing PPARy levels.”

What the sources say

• Disputed

  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.

  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 sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

“BACE1 inhibition can restore insulin signaling in this setting, while mimicked by sAPPβ.”

What the sources say

• Supported

  In Results section 3.2 (p. 12), BACE1 inhibition with M3 reversed palmitate’s reduction of insulin-stimulated Akt phosphorylation and prevented changes in other insulin-signaling markers. The Discussion (p. 18) says BACE1 inhibition attenuated palmitate-induced ER stress, inflammation, and insulin resistance, while sAPPβ mimicked most of palmitate’s effects. (LLM, conf=0.93)

  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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Partly supported

  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)

  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 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Results section, “BACE1 is phosphorylated by p25/Cdk5 at Thr252,” identifies Thr252 as the phosphorylation site. The Results section, “p25/Cdk5-mediated phosphorylation of BACE1 increases BACE1 activity,” reports that phosphorylated BACE1 had 20% higher enzymatic activity than unphosphorylated BACE1 in vitro. (LLM, conf=0.94)

  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

In the paper

“The BACE1 promotor has an NFκB binding site. When phosphorylated, NFκB increases BACE1 promotor activity and transcription.”

What the sources say

• Partly supported

  The sections on NF-κB-binding elements and BACE1 promoter activity report that NF-κB p65 binds elements in the human BACE1 promoter and increases its activity. The section on BACE1 gene transcription reports increased BACE1 mRNA with p65 expression. These passages do not establish that phosphorylation of NF-κB is the condition that produces those effects; page numbers were not supplied. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly supported

  The Introduction and Discussion report greater weight gain, hyperphagia, hyperinsulinemia, and insulin resistance in BACE2-knockout mice fed a high-fat diet. The Results also report impaired leptin sensitivity. The claim omits the obesogenic-diet condition that bounds the reported adverse metabolic phenotype. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, both BACE1 knockout and inhibitor‐treated mice show no change in daily food intake while presenting with decreased body weight”

What the sources say

• Partly supported

  The Results section ('BACE1−/− mice have decreased body weight and adiposity'; page unavailable) reports lower body mass and unchanged cumulative food intake in knockout mice. It does not establish unchanged daily intake or lower body weight in inhibitor-treated mice: the Methods ('Cell culture'; page unavailable) describe inhibitor treatment of cells, not mice. (LLM, conf=0.90)

  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 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion states that Bace1 knockout mice had unchanged daily food intake on either regular chow or a high-fat diet despite lower body weight. The Results report that Bace1 inhibitor treatment reduced body weight without changing food intake in diet-induced obese mice. (LLM, conf=0.94)

  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

In the paper

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

What the sources say

• Partly supported

  The Discussion says statins may reduce β-amyloid formation by lowering cholesterol. It does not mention BACE1 or establish that cholesterol regulates BACE1, so the claimed mechanism is unsupported by this paper. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Supporting this, BACE1 knock‐in was found to increase adipogenesis, hyperleptinemia, PTP1B, and ER stress.”

What the sources say

• Supported

  The Discussion says neuronal hBACE1 expression promoted adipogenesis and induced hyperleptinaemia. The Results report upregulated PTP1B in PLB4 mouse liver and increased hypothalamic ER-stress markers compared with controls. (LLM, conf=0.93)

  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

In the paper

“L1 cell adhesion molecule (L1CAM) and neural cell adhesion molecule L1‐like protein (CHL1) are BACE1 substrates involved in axon guidance.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yet

  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
• Not checked yet

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• Not checked yet

  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

In the paper

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

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“Overexpression of BACE1 has been shown to decrease CREB phosphorylation, in turn decreasing protein kinase A (PKA) activity, and cyclic adenosine monophosphate (cAMP) levels.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

In the paper

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

In the paper

“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”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Not checked yet

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

  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
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• Not checked yetcites [48] Araki W. Post‐translational regulation of the β‐secretase BACE1. Brain Res Bull. 2016; 126(Pt 2): 170‐ 177. 27086128

In the paper

“BACE1 activity is regulated at the transcriptional, post‐transcriptional, and translation level, with post‐translational modifications (PTMs) required to produce the mature BACE1 protein.”

What the sources say

• Not checked yetcites [48] Araki W. Post‐translational regulation of the β‐secretase BACE1. Brain Res Bull. 2016; 126(Pt 2): 170‐ 177. 27086128

In the paper

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

What the sources say

• Not checked yet

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

  cites [104] Zhou Y, Rui L. Leptin signaling and leptin resistance. Front Med. 2013; 7(2): 207‐ 222. 23580174 PMC4069066 source
• Not checked yetcites [105] Ahima RS. Revisiting leptin's role in obesity and weight loss. J Clin Invest. 2008; 118(7): 2380‐ 2383. 18568083 PMC2430504
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• Not checked yetcites [82] WHO. Diabetes. https://www.who.int/news-room/fact-sheets/detail/diabetes. Published 2020. Accessed 24th February 2021.

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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
• Not checked yetcites [87] Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes. Diabetes. 2007; 56(8): 2028‐ 2035. 17563065

In the paper

“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.”

In the paper

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

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• ?Not matched

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“It is clear that the BACE1‐AS/BACE1/Aβ axis has important physiological functions outside the brain.”

In the paper

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

What the sources say

• Not checked yet

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

  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

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“Despite showing a reduction in cerebrospinal fluid Aβ levels to 63%–81%, no beneficial effect on cognition was observed for Verubecestat.”

What the sources say

• ?Not matched

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

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

In the paper

“Furthermore, the dysregulation of the BACE1/BACE1‐AS/Aβ axis is associated with heart failure, with both BACE1‐AS and BACE1 found upregulated.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“Furthermore, plasma BACE1 protein levels are elevated in people with T2D and correlate with glycemic control, independently of cognition.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yet

  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

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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
• ?Not checked — no full text of the sourcecites [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