The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.

Aged Aged, 80 and over Alzheimer Disease / prevention & control Amyloid Precursor Protein Secretases / antagonists & inhibitors Amyloid beta-Protein Precursor / metabolism Aspartic Acid Endopeptidases / antagonists & inhibitors Clinical Trials, Phase II as Topic Clinical Trials, Phase III as Topic Enzyme Inhibitors / therapeutic use Female Humans Male Middle Aged Plaque, Amyloid / prevention & control Research Design

Journal

Nature reviews. Neurology
ISSN: 1759-4766
Titre abrégé: Nat Rev Neurol
Pays: England
ID NLM: 101500072

Informations de publication

Date de publication:
11 2021
Historique:
accepted: 23 07 2021
pubmed: 23 9 2021
medline: 21 1 2022
entrez: 22 9 2021
Statut: ppublish

Résumé

Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor; preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.

Identifiants

DOI: 10.1038/s41582-021-00545-1 PMID: 34548654
pubmed: 34548654
doi: 10.1038/s41582-021-00545-1
pii: 10.1038/s41582-021-00545-1
doi:

Substances chimiques

APP protein, human 0
Amyloid beta-Protein Precursor 0
Enzyme Inhibitors 0
Amyloid Precursor Protein Secretases EC 3.4.-
Aspartic Acid Endopeptidases EC 3.4.23.-
BACE1 protein, human EC 3.4.23.46

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

703-714

Subventions

Organisme : NIA NIH HHS
ID : R01AG053267-S2
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG053267
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046179
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG042791
Pays : United States
Organisme : NIA NIH HHS
ID : R01AG053267-S1
Pays : United States
Organisme : NIA NIH HHS
ID : U01AG42791-S1
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG059798
Pays : United States

Informations de copyright

© 2021. Springer Nature Limited.

Références

Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).
pubmed: 27025652 pmcid: 4888851 doi: 10.15252/emmm.201606210
De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).
pubmed: 26871627 doi: 10.1016/j.cell.2015.12.056
Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as beta-secretase. Mol. Cell. Neurosci. 14, 419–427 (1999).
pubmed: 10656250 doi: 10.1006/mcne.1999.0811
Sinha, S. et al. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 402, 537–540 (1999).
pubmed: 10591214 doi: 10.1038/990114
Vassar, R. et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735–741 (1999).
pubmed: 10531052 doi: 10.1126/science.286.5440.735
Yan, R. et al. Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402, 533–537 (1999).
pubmed: 10591213 doi: 10.1038/990107
Das, B. & Yan, R. A close look at BACE1 inhibitors for Alzheimer’s disease treatment. CNS Drugs 33, 251–263 (2019).
pubmed: 30830576 pmcid: 7330928 doi: 10.1007/s40263-019-00613-7
Egan, M. F. et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N. Engl. J. Med. 380, 1408–1420 (2019).
pubmed: 30970186 pmcid: 6776078 doi: 10.1056/NEJMoa1812840
Henley, D. et al. Preliminary results of a trial of atabecestat in preclinical Alzheimer’s disease. N. Engl. J. Med. 380, 1483–1485 (2019).
pubmed: 30970197 doi: 10.1056/NEJMc1813435
Knopman, D. S. Lowering of amyloid-beta by beta-secretase inhibitors - some informative failures. N. Engl. J. Med. 380, 1476–1478 (2019).
pubmed: 30970194 doi: 10.1056/NEJMe1903193
Doody, R. S. et al. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N. Engl. J. Med. 369, 341–350 (2013).
pubmed: 23883379 doi: 10.1056/NEJMoa1210951
Coric, V. et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch. Neurol. 69, 1430–1440 (2012).
pubmed: 22892585 doi: 10.1001/archneurol.2012.2194
De Strooper, B. Lessons from a failed gamma-secretase Alzheimer trial. Cell 159, 721–726 (2014).
pubmed: 25417150 doi: 10.1016/j.cell.2014.10.016
Kevin, D. et al. Preclinical validation of a potent γ-secretase modulator for Alzheimer’s disease prevention. J. Exp. Med. 218, e20202560 (2021).
doi: 10.1084/jem.20202560
Graf, A. et al. Umibecestat in the API Generation program: worsening in RBANS and/or CDR on treatment reverses after wash-out. Alzheimers Dement. 16, e041140 (2020).
doi: 10.1002/alz.041140
Hampel, H. et al. Precision pharmacology for Alzheimer’s disease. Pharmacol. Res. 130, 331–365 (2018).
pubmed: 29458203 pmcid: 8505114 doi: 10.1016/j.phrs.2018.02.014
Eketjall, S. et al. AZD3293: a novel, orally active BACE1 inhibitor with high potency and permeability and markedly slow off-rate kinetics. J. Alzheimers Dis. 50, 1109–1123 (2016).
pubmed: 26890753 pmcid: 4927864 doi: 10.3233/JAD-150834
Kennedy, M. E. et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer’s disease patients. Sci. Transl Med. 8, 363ra150 (2016).
pubmed: 27807285 doi: 10.1126/scitranslmed.aad9704
Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 10, e9316 (2018).
pubmed: 30224383 pmcid: 6220303 doi: 10.15252/emmm.201809316
Egan, M. F. et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N. Engl. J. Med. 378, 1691–1703 (2018).
pubmed: 29719179 pmcid: 6776074 doi: 10.1056/NEJMoa1706441
Wessels, A. M. 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. 77, 199–209 (2019).
pmcid: 6902191 doi: 10.1001/jamaneurol.2019.3988
Mintun, M. A. et al. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 384, 1691–1704 (2021).
pubmed: 33720637 doi: 10.1056/NEJMoa2100708
Koskinas, K. C. et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur. Heart J. 39, 1172–1180 (2018).
pubmed: 29069377 doi: 10.1093/eurheartj/ehx566
Zuhl, A. M. et al. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of beta-secretase inhibitors. Nat. Commun. 7, 13042 (2016).
pubmed: 27727204 pmcid: 5062570 doi: 10.1038/ncomms13042
Cai, J. et al. β-Secretase (BACE1) inhibition causes retinal pathology by vascular dysregulation and accumulation of age pigment. EMBO Mol. Med. 4, 980–991 (2012).
pubmed: 22903875 pmcid: 3491829 doi: 10.1002/emmm.201101084
Eli Lilly & Company. Lilly voluntarily terminates phase II study for LY2886721, a beta secretase inhibitor being investigated as a treatment for Alzheimer’s disease. Lilly https://investor.lilly.com/static-files/32b60234-ea3c-4461-875d-87167528f516 (2013).
Esterhazy, D. et al. Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab. 14, 365–377 (2011).
pubmed: 21907142 doi: 10.1016/j.cmet.2011.06.018
Stutzer, I. et al. Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta-cells. J. Biol. Chem. 288, 10536–10547 (2013).
pubmed: 23430253 pmcid: 3624435 doi: 10.1074/jbc.M112.444703
Voytyuk, I. et al. BACE2 distribution in major brain cell types and identification of novel substrates. Life Sci. Alliance 1, e201800026 (2018).
pubmed: 30456346 pmcid: 6238391 doi: 10.26508/lsa.201800026
Farzan, M., Schnitzler, C. E., Vasilieva, N., Leung, D. & Choe, H. BACE2, a beta -secretase homolog, cleaves at the beta site and within the amyloid-beta region of the amyloid-beta precursor protein. Proc. Natl Acad. Sci. USA 97, 9712–9717 (2000).
pubmed: 10931940 pmcid: 16930 doi: 10.1073/pnas.160115697
Yan, R., Munzner, J. B., Shuck, M. E. & Bienkowski, M. J. BACE2 functions as an alternative alpha-secretase in cells. J. Biol. Chem. 276, 34019–34027 (2001).
pubmed: 11423558 doi: 10.1074/jbc.M105583200
Rochin, L. et al. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc. Natl Acad. Sci. USA 110, 10658–10663 (2013).
pubmed: 23754390 pmcid: 3696817 doi: 10.1073/pnas.1220748110
Cebers, G. et al. Reversible and species-specific depigmentation effects of AZD3293, a BACE inhibitor for the treatment of Alzheimer’s disease, are related to BACE2 inhibition and confined to epidermis and hair. J. Prev. Alzheimers Dis. 3, 202–218 (2016).
pubmed: 29199322
Shimshek, D. R. et al. Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice. Sci. Rep. 6, 21917 (2016).
pubmed: 26912421 pmcid: 4766495 doi: 10.1038/srep21917
Kuhn, P. H. et al. Secretome protein enrichment identifies physiological BACE1 protease substrates in neurons. EMBO J. 31, 3157–3168 (2012).
pubmed: 22728825 pmcid: 3400020 doi: 10.1038/emboj.2012.173
Zhou, L. et al. The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo. J. Biol. Chem. 287, 25927–25940 (2012).
pubmed: 22692213 pmcid: 3406677 doi: 10.1074/jbc.M112.377465
Hemming, M. L., Elias, J. E., Gygi, S. P. & Selkoe, D. J. Identification of beta-secretase (BACE1) substrates using quantitative proteomics. PLoS ONE 4, e8477 (2009).
pubmed: 20041192 pmcid: 2793532 doi: 10.1371/journal.pone.0008477
Tüshaus, J. et al. An optimized quantitative proteomics method establishes the cell type-resolved mouse brain secretome. EMBO J. 39, e105693 (2020).
pubmed: 32954517 pmcid: 7560198 doi: 10.15252/embj.2020105693
Rogers, M. B. Bump in the road or disaster? BACE inhibitors worsen cognition. AlzForum https://www.alzforum.org/news/conference-coverage/bump-road-or-disaster-bace-inhibitors-worsen-cognition (2018).
Egan, M. F. 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. 11, 68 (2019).
pubmed: 31387606 pmcid: 6685277 doi: 10.1186/s13195-019-0520-1
Lopez Lopez, C. et al. The Alzheimer’s Prevention Initiative Generation Program: study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer’s disease. Alzheimers Dement. 5, 216–227 (2019).
doi: 10.1016/j.trci.2019.02.005
Sperling, R. et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: a truncated randomized phase 2b/3 clinical trial. JAMA Neurol. 78, 293–301 (2021).
pubmed: 33464300 doi: 10.1001/jamaneurol.2020.4857
Wessels, A. M. et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer’s disease. Alzheimers Dement. 16, 1483–1492 (2020).
pubmed: 33049114 doi: 10.1002/alz.12164
Timmers, M. et al. Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer’s disease: randomized, double-blind, placebo-controlled study. Alzheimers Res. Ther. 10, 85 (2018).
pubmed: 30134967 pmcid: 6106931 doi: 10.1186/s13195-018-0415-6
Lynch, S. Y. et al. Elenbecestat, a BACE inhibitor: results from a phase 2 study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer’s disease [abstract P4-389]. Alzheimers Dement. 14, 1623 (2018).
doi: 10.1016/j.jalz.2018.07.213
Willis, B. et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of LY3202626, a novel BACE1 inhibitor, in healthy subjects and patients with Alzheimer’s disease [abstract P1-044]. Alzheimers Dement. 12, 418 (2016).
Rogers, M. B. Picking through the rubble, field tries to salvage BACE inhibitors. AlzForum https://www.alzforum.org/news/conference-coverage/picking-through-rubble-field-tries-salvage-bace-inhibitors (2019).
Reiman, E. M. et al. The API Generation program: umibecestat treatment and discontinuation effects on hippocampal and whole brain volumes in the overall population and amyloid-negative APOE4 homozygotes. Alzheimers Dement. 16, e041142 (2020).
doi: 10.1002/alz.041142
Sur, C. et al. BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer’s disease brain. Brain 143, 3816–3826 (2020).
pubmed: 33253354 pmcid: 8453290 doi: 10.1093/brain/awaa332
McConlogue, L. et al. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J. Biol. Chem. 282, 26326–26334 (2007).
pubmed: 17616527 doi: 10.1074/jbc.M611687200
Cao, L., Rickenbacher, G. T., Rodriguez, S., Moulia, T. W. & Albers, M. W. The precision of axon targeting of mouse olfactory sensory neurons requires the BACE1 protease. Sci. Rep. 2, 231 (2012).
pubmed: 22355745 pmcid: 3262176 doi: 10.1038/srep00231
Dominguez, D. et al. Phenotypic and biochemical analyses of BACE1- and BACE2-deficient mice. J. Biol. Chem. 280, 30797–30806 (2005).
pubmed: 15987683 doi: 10.1074/jbc.M505249200
Laird, F. M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J. Neurosci. 25, 11693–11709 (2005).
pubmed: 16354928 pmcid: 2564291 doi: 10.1523/JNEUROSCI.2766-05.2005
Hu, X., Das, B., Hou, H., He, W. & Yan, R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J. Exp. Med. 215, 927–940 (2018).
pubmed: 29444819 pmcid: 5839766 doi: 10.1084/jem.20171831
Lombardo, S. et al. BACE1 partial deletion induces synaptic plasticity deficit in adult mice. Sci. Rep. 9, 19877 (2019).
pubmed: 31882662 pmcid: 6934620 doi: 10.1038/s41598-019-56329-7
Barao, S. et al. Antagonistic effects of BACE1 and APH1B-gamma-secretase control axonal guidance by regulating growth cone collapse. Cell Rep. 12, 1367–1376 (2015).
pubmed: 26299962 pmcid: 4820248 doi: 10.1016/j.celrep.2015.07.059
Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012).
pubmed: 22801501 doi: 10.1038/nature11283
Martiskainen, H. et al. Decreased plasma beta-amyloid in the Alzheimer’s disease APP A673T variant carriers. Ann. Neurol. 82, 128–132 (2017).
pubmed: 28556232 doi: 10.1002/ana.24969
Maloney, J. A. et al. Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein. J. Biol. Chem. 289, 30990–31000 (2014).
pubmed: 25253696 pmcid: 4223305 doi: 10.1074/jbc.M114.589069
Das, P. et al. Transient pharmacologic lowering of Abeta production prior to deposition results in sustained reduction of amyloid plaque pathology. Mol. Neurodegener. 7, 39 (2012).
pubmed: 22892055 pmcid: 3477045 doi: 10.1186/1750-1326-7-39
Jack, C. R. et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).
pubmed: 29653606 pmcid: 5958625 doi: 10.1016/j.jalz.2018.02.018
Sevigny, J. et al. The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).
pubmed: 27582220 doi: 10.1038/nature19323
Mills, S. M. et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev. Neurol. 169, 737–743 (2013).
pubmed: 24016464 doi: 10.1016/j.neurol.2013.07.017
Reiman, E. M. et al. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 26, 321–329 (2011).
pubmed: 21971471 pmcid: 3343739 doi: 10.3233/JAD-2011-0059
Sperling, R. A. et al. The A4 study: stopping AD before symptoms begin? Sci. Transl Med. 6, 228fs213 (2014).
doi: 10.1126/scitranslmed.3007941
Tariot, P. N. et al. The generation program: baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation study 1 and Generation study 2. Alzheimers Dement. 16, e041139 (2020).
doi: 10.1002/alz.041139
Rouzade-Dominguez, M.-L. et al. The API Generation program: biomarker phenotyping of cognitively unimpaired participants screened in Generation study 1 and Generation study 2. Alzheimers Dement. 16, e041143 (2020).
doi: 10.1002/alz.041143
Karlnoski, R. A. et al. Suppression of amyloid deposition leads to long-term reductions in Alzheimer’s pathologies in Tg2576 mice. J. Neurosci. 29, 4964–4971 (2009).
pubmed: 19369565 pmcid: 2688812 doi: 10.1523/JNEUROSCI.4560-08.2009
Uhlmann, R. E. et al. Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life. Nat. Neurosci. 23, 1580–1588 (2020).
pubmed: 33199898 pmcid: 7783656 doi: 10.1038/s41593-020-00737-w
Mortamais, M. et al. Detecting cognitive changes in preclinical Alzheimer’s disease: a review of its feasibility. Alzheimers Dement. 13, 468–492 (2017).
pubmed: 27702618 doi: 10.1016/j.jalz.2016.06.2365
Brown, M. S. & Goldstein, J. L. A tribute to Akira Endo, discoverer of a “penicillin” for cholesterol. Atheroscler. Suppl. 5, 13–16 (2004).
doi: 10.1016/j.atherosclerosissup.2004.08.007
Golde, T. E., Schneider, L. S. & Koo, E. H. Anti-aβ therapeutics in Alzheimer’s disease: the need for a paradigm shift. Neuron 69, 203–213 (2011).
pubmed: 21262461 pmcid: 3058906 doi: 10.1016/j.neuron.2011.01.002
Cummings, J., Lee, G., Ritter, A., Sabbagh, M. & Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. 5, 272–293 (2019).
doi: 10.1016/j.trci.2019.05.008
Lewcock, J. W. et al. Emerging microglia biology defines novel therapeutic approaches for Alzheimer’s disease. Neuron 108, 801–821 (2020).
pubmed: 33096024 doi: 10.1016/j.neuron.2020.09.029
Panza, F., Lozupone, M., Logroscino, G. & Imbimbo, B. P. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 15, 73–88 (2019).
pubmed: 30610216 doi: 10.1038/s41582-018-0116-6
Donohue, M. C. et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 71, 961–970 (2014).
pubmed: 24886908 pmcid: 4439182 doi: 10.1001/jamaneurol.2014.803
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02569398 (2020).
Wang, J. et al. ADCOMS: A composite clinical outcome for prodromal Alzheimer’s disease trials. J. Neurol. Neurosurg. Psychiatry 87, 993–999 (2016).
pubmed: 27010616 doi: 10.1136/jnnp-2015-312383
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02956486 (2021).
Mohs, R. C. et al. Development of cognitive instruments for use in clinical trials of antidementia drugs: additions to the Alzheimer’s Disease Assessment Scale that broaden its scope. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis. Assoc. Disord. 11, S13–S21 (1997).
pubmed: 9236948 doi: 10.1097/00002093-199700112-00003
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02245737 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02783573 (2019).
McKinzie, D. et al. Nonclinical pharmacological characterization of the BACE1 inhibitor LY3202626. Alzheimers Dement. 12, P432–P433 (2016).
doi: 10.1016/j.jalz.2016.06.828
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02791191 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03367403 (2021).
Hsiao, C. C., Rombouts, F. & Gijsen, H. J. M. New evolutions in the BACE1 inhibitor field from 2014 to 2018. Bioorg. Med. Chem. Lett. 29, 761–777 (2019).
pubmed: 30709653 doi: 10.1016/j.bmcl.2018.12.049
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02565511 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01739348 (2018).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01953601 (2019).
Navitsky, M. et al. Standardization of amyloid quantitation with florbetapir standardized uptake value rations to the Centiloid scale. Alzheimers Dement. 14, 1565–1571 (2018).
pubmed: 30006100 doi: 10.1016/j.jalz.2018.06.1353
Chávez-Gutiérrez, L. & Szaruga, M. Mechanisms of neurodegeneration - insights from familial Alzheimer’s disease. Semin. Cell Dev. Biol. 105, 75–85 (2020).
pubmed: 32418657 doi: 10.1016/j.semcdb.2020.03.005
Güner, G. & Lichtenthaler, S. F. The substrate repertoire of γ-secretase/presenilin. Semin. Cell Dev. Biol. 105, 27–42 (2020).
pubmed: 32616437 doi: 10.1016/j.semcdb.2020.05.019
Lichtenthaler, S. F., Lemberg, M. K. & Fluhrer, R. Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. EMBO J. 37, e99456 (2018).
pubmed: 29976761 pmcid: 6068445 doi: 10.15252/embj.201899456
Jorissen, E. et al. The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. J. Neurosci. 30, 4833–4844 (2010).
pubmed: 20371803 pmcid: 2921981 doi: 10.1523/JNEUROSCI.5221-09.2010
Kuhn, P. H. et al. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 29, 3020–3032 (2010).
pubmed: 20676056 pmcid: 2944055 doi: 10.1038/emboj.2010.167
Lammich, S. et al. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc. Natl Acad. Sci. USA 96, 3922–3927 (1999).
pubmed: 10097139 pmcid: 22396 doi: 10.1073/pnas.96.7.3922
Willem, M. et al. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature 526, 443–447 (2015).
pubmed: 26322584 pmcid: 6570618 doi: 10.1038/nature14864
Zhang, Z. et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat. Commun. 6, 8762 (2015).
pubmed: 26549211 doi: 10.1038/ncomms9762
Saftig, P. & Lichtenthaler, S. P. The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog. Neurobiol. 135, 1–20 (2015).
pubmed: 26522965 doi: 10.1016/j.pneurobio.2015.10.003
Ou-Yang, M. H. et al. Axonal organization defects in the hippocampus of adult conditional BACE1 knockout mice. Sci. Transl Med. 10, e5620 (2018).
doi: 10.1126/scitranslmed.aao5620
Cheret, C. et al. Bace1 and neuregulin-1 cooperate to control formation and maintenance of muscle spindles. EMBO J. 32, 2015–2028 (2013).
pubmed: 23792428 pmcid: 3715864 doi: 10.1038/emboj.2013.146
Fleck, D. et al. Dual cleavage of neuregulin 1 type III by BACE1 and ADAM17 liberates its EGF-like domain and allows paracrine signaling. J. Neurosci. 33, 7856–7869 (2013).
pubmed: 23637177 pmcid: 6618983 doi: 10.1523/JNEUROSCI.3372-12.2013
Willem, M. et al. Control of peripheral nerve myelination by the beta-secretase BACE1. Science 314, 664–666 (2006).
pubmed: 16990514 doi: 10.1126/science.1132341
Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 9, 1520–1525 (2006).
pubmed: 17099708 doi: 10.1038/nn1797
Hu, X., He, W., Luo, X., Tsubota, K. E. & Yan, R. BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep. 4, 40–49 (2013).
pubmed: 23831026 pmcid: 3740554 doi: 10.1016/j.celrep.2013.06.005
Zhu, K. et al. Beta-site amyloid precursor protein cleaving enzyme 1 inhibition impairs synaptic plasticity via seizure protein 6. Biol. Psychiatry 83, 428–437 (2018).
pubmed: 28129943 doi: 10.1016/j.biopsych.2016.12.023
Pigoni, M. et al. Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons. Mol. Neurodegener. 11, 67 (2016).
pubmed: 27716410 pmcid: 5053352 doi: 10.1186/s13024-016-0134-z
Hitt, B. et al. beta-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J. Biol. Chem. 287, 38408–38425 (2012).
pubmed: 22988240 pmcid: 3493884 doi: 10.1074/jbc.M112.415505
Muller, T. et al. Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons. EMBO J. 37, e98858 (2018).
pubmed: 30049711 pmcid: 6120667 doi: 10.15252/embj.201798858
Wang, Y. N. et al. Controlling of glutamate release by neuregulin3 via inhibiting the assembly of the SNARE complex. Proc. Natl Acad. Sci. USA 115, 2508–2513 (2018).
pubmed: 29463705 pmcid: 5877931 doi: 10.1073/pnas.1716322115

Auteurs

Eric McDade (E)

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA. ericmcdade@wustl.edu.
ORCID: 0000-0002-6764-3866

Iryna Voytyuk (I)

Department of Neurosciences, KU Leuven, Leuven, Belgium.
Centre for Brain and Disease Research, VIB (Flanders Institute for Biotechnology), Leuven, Belgium.
ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge, UK.

Paul Aisen (P)

Alzheimer's Therapeutic Research Institute, University of Southern California, Los Angeles, CA, USA.

Randall J Bateman (RJ)

Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
ORCID: 0000-0002-7729-1702

Maria C Carrillo (MC)

Alzheimer's Association, Chicago, IL, USA.
ORCID: 0000-0003-3057-2387

Bart De Strooper (B)

Department of Neurosciences, KU Leuven, Leuven, Belgium.
Centre for Brain and Disease Research, VIB (Flanders Institute for Biotechnology), Leuven, Belgium.
Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, UK.

Christian Haass (C)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Biomedical Center, Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.

Eric M Reiman (EM)

Banner Alzheimer's Institute, Phoenix, AZ, USA.
ORCID: 0000-0002-0705-3696

Reisa Sperling (R)

Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Pierre N Tariot (PN)

Banner Alzheimer's Institute, Phoenix, AZ, USA.
ORCID: 0000-0002-6058-8032

Riqiang Yan (R)

Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA.

Colin L Masters (CL)

The Florey Institute, The University of Melbourne, Parkville, VIC, Australia.

Robert Vassar (R)

Davee Department of Neurology, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. r-vassar@northwestern.edu.

Stefan F Lichtenthaler (SF)

German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. stefan.lichtenthaler@dzne.de.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. stefan.lichtenthaler@dzne.de.
Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. stefan.lichtenthaler@dzne.de.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Démence › Maladie d'Alzheimer › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Endopeptidases › Amyloid precursor protein secretases › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines sécrétoires inhibitrices de protéinases › Protéase nexines › Précurseur de la protéine bêta-amyloïde › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › Endopeptidases › Aspartic acid endopeptidases › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études cliniques comme sujet › Essais cliniques comme sujet › Essais cliniques de phase II comme sujet › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études cliniques comme sujet › Essais cliniques comme sujet › Essais cliniques de phase III comme sujet › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › États, signes et symptômes pathologiques › États anatomopathologiques › Plaque amyloïde › The case for low-level BACE1 inhibition for...
questionsmedicales.fr › Disciplines des sciences naturelles › Science › Recherche › Plan de recherche › The case for low-level BACE1 inhibition for...