Journal of Biological Chemistry, Год журнала: 2021, Номер 296, С. 100489 - 100489

Опубликована: Янв. 1, 2021

Genetic, biochemical, and anatomical grounds led to the proposal of amyloid cascade hypothesis centered on accumulation beta peptides (Aβ) explain Alzheimer's disease (AD) etiology. In this context, a bulk efforts have aimed at developing therapeutic strategies seeking reduce Aβ levels, either by blocking its production (γ- β-secretase inhibitors) or neutralizing it once formed (Aβ-directed immunotherapies). However, so far vast majority of, if not all, clinical trials based these failed, since they been able restore cognitive function in AD patients, even many cases, worsened picture. We here propose that could be more complex than simple Aβ-linked pathology discuss possibility way reconcile undoubted genetic evidences linking processing APP consistent failure Aβ-based envision pathological contribution direct precursor Aβ, β-secretase-derived C-terminal fragment APP, βCTF, also referred as C99. review, we summarize scientific pointing C99 an early contributor postulate γ-secretase should considered only Aβ-generating protease, but beneficial C99-inactivating enzyme. sense, limitations molecules targeting alternative levels other means notably enhancing lysosomal degradation. is most frequent age-related neurodegenerative disease. After initial characterization, histopathological analysis revealed presence two major lesions signing pathology: senile plaques are extracellular protein aggregates neurofibrillary tangles intracellular neuronal (1Calderon-Garciduenas A.L. Duyckaerts C. Alzheimer disease.Handbook Clin. 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Nervenarzt. 90: 884-890Crossref It remains before "throwing out baby bath water," try failures trials. observations envisage possible APP-derived fragments itself growing proposes (see below), fragment, C99, main AD. address Aβ-centric explained, least partly, their lack effect To go further, describe clues suggesting enzyme argument instead circumvent accumulation, which would then advantage levels.Table 1Principal antiamyloid drugs strategiesStrategyDrug/specific targetAβ modulation treated patientsFDA statute participantsSide effects/cognitive readoutReferenceActive immunotherapyAN-1792 (synthetic Aβ42, Janssen)≥ 60–70% reduction brain (post-mortem immonustaining)Discontinued 2002 (mild moderate patients)Meningoencephalitis(208Nicoll J.A.R. Wilkinson Holmes Steart Markham Weller R.O. Neuropathology after immunization amyloid-b peptide: report.Nat. Med. 2003; 9: 448-452Crossref Scholar)(209Holmes Boche Yadegarfar Hopkins V. Bayer Jones R.W. Bullock Love Neal J.W. Zotova Nicoll Long-term effects Abeta42 immunisation Follow-up randomised, placebo-controlled phase I trial.Lancet. 2008; 372: 216-223Abstract (1113) Scholar)(210Boche Donald Harris Reduction aggregated Tau processes bodies disease.Acta Neuropathol. 2010; 13-20Crossref Scholar)CAD106 (multiple copies Aβ1-6 peptide, Novartis)1.3% PET scan (florbetapir)2–3-fold increase plasma Aβ40 450 mgDiscontinued 2019 (asymptomatic carriers APOE-4)Worsens cognition, headache, nasopharyngitis, pyrexia, hypertension, back pain…(211Vandenberghe Riviere M.E. Caputo Sovago Maguire R.P. Farlow Marotta Sanchez-Valle Scheltens Ryan Graf Active Abeta immunotherapy CAD106 2b study.Alzheimers Dement. (N. Y.). 10-22Abstract Scholar)Passive immunotherapyCrenezumab (monomers, oligomers, fibrils Roche)≥ 70% Aβ42 CSF 15 mg/kgPhase II ongoing asymptomatic PS mutationsLack efficacyin mild AD(212Cummings J.L. Cohen van Dyck C.H. Brody Curtis Cho Ward Friesenhahn Rabe Brunstein Quartino Honigberg L.A. Fuji R.N. Clayton Mortensen al.Abby: 2 randomized trial crenezumab disease.Neurology. 2018; e1889-e1897Crossref (27) Scholar)Solanezumab (monomeric soluble Eli Lilly)170- 18-fold respectively no (florbetapir) 400 mgPhase III people who biomarker depositionLack ADand mutations(213Honig L.S. Vellas Woodward Boada Borrie Hager Andreasen Scarpini Liu-Seifert Case Dean Hake Sundell Poole Hoffmann al.Trial solanezumab disease.N. Engl. 378: 321-330Crossref (399) Scholar)Aducanumab (oligomers, Biogen)80% 10 open-label extension study patientsOne (EMERGE) positive significant biologics license application submitted FDA approval July 2020www.alzforum.org/therapeutics/aducanumabGantenerumab 15%, 35% 78% 60, 200 1200 mg respectivelyPhase (SCarlet RoAD, Marguerite GRADUATE) (Dian-Tu)A directional trend slower AD(214Ostrowitzki Deptula Thurfjell Barkhof Bohrmann Brooks Klunk W.E. Ashford Yoo Xu Z.X. Loetscher Santarelli Mechanism removal gantenerumab.Arch. 69: 198-207Crossref (282) Scholar)(215Klein Delmar Voyle Rehal Hofmann Abi-Saab Andjelkovic Ristic Wang Bateman Kerchner Baudler Fontoura Doody Gantenerumab reduces amyloid-beta prodromal substudy interim analysis.Alzheimers Ther. 11: 101Crossref (19) Scholar)BAN2401 (soluble protofibrils, Biogen)≥ 120% plasma300 fold CSF93% symptomatic (Clarity AD) deposition (AHEAD 3–45)47% 30% judged ADAS-Cog ADCOMS respetively(216Logovinsky Satlin Lai Swanson Kaplow Osswald Basun Safety tolerability BAN2401--a protofibril selective antibody.Alzheimers 2016; 8: 14Crossref Scholar)www.alzforum.org/therapeutics/ban2401β-secretase inhibitorsVerubecestat (MK-8931Merck)≥ 57–84% 12–60 2018 (prodromal, patients)Worsens anxiety, depression, sleep problems(217Kennedy Stamford A.W. Chen X. Cox Cumming J.N. Dockendorf M.F. Egan Ereshefsky Hodgson Hyde Jhee Kleijn H.J. Kuvelkar Mattson B.A. al.The inhibitor verubecestat (MK-8931) CNS patients.Sci. Transl. 363ra150Crossref Scholar)(218Egan Kost Voss Mukai Aisen P.S. Cummings Tariot P.N. Zhang Furtek Mahoney Harper Mozley al.Randomized 380: 1408-1420Crossref (196) Scholar)Atabecestat (Janssen)≥ 67–90% 10–50 people)Worsens elevated liver enzymes, problems(219Timmers Streffer J.R. Russu Tominaga Shimizu Shiraishi Tatikola Smekens Borjesson-Hanson Matias-Guiu Baquero Tesseur Tritsmans al.Pharmacodynamics atabecestat (JNJ-54861911), oral Randomized, double-blind, 10: 85Crossref Scholar)(220Henley Raghavan Sperling Raman Romano Preliminary results preclinical 1483-1485Crossref (88) Scholar)Lanabecestat (AZD3293,Eli Lilly)≥64% 15–50 mg≥51% 76% (prodromal patients)Lack efficacy neuropsychiatric adverse events, weight loss, hair color changes(221Cebers Alexander R.C. Haeberlein S.B. Han Goldwater Olsson Ye Rosen Russell Maltby Eketjall Kugler A.R. AZD3293: Pharmacokinetic pharmacodynamic healthy subjects Alzheimers Dis. 55: 1039-1053Crossref (48) Scholar)(222Wessels A.M. Zimmer Selzler K.J. Bragg Andersen S.W. Landry Krull Downing Willis Shcherbinin Mullen Barker Schumi Shering al.Efficacy safety Lanabecestat treatment AMARANTH DAYBREAK-ALZ trials.JAMA 77: 199-209Crossref (39) Scholar)Umibecestat (Novartis)≥ 90% 85 atrophy loss(223Neumann U. Ufer Jacobson L.H. Rouzade-Dominguez M.L. Huledal Kolly Luond R.M. Machauer Veenstra S.J. Hurth Rueeger Tintelnot-Blomley Staufenbiel Shimshek D.R. Perrot BACE-1 CNP520 prevention disease.EMBO Mol. 10Crossref Scholar)(187Lopez Lopez Langbaum J.B. Langlois Zalesak Hendrix Thomas R.G. Viglietta Lenz Prevention Initiative Generation Program: Study design controlled individuals risk onset disease.Alzheimers (N Y). 5: 216-227Abstract (21) www.alzforum.org/therapeutics/umibecestatElenbecestat (Biogen)≥5.8% ≥13.6% (florbetaben florbetapir respectively) 50 patients)Weight skin rashes events(224Lynch S.Y. Dhadda Luthman Albala Elenbecestat, E2609, Bace inhibitor: Results phase-2 impairment mild-to-moderate disease.Alzheimer's P1623Abstract Scholar)(225Imbimbo Watling Investigational BACE disease.Expert Investig. Drugs. 28: 967-975Crossref (36) Scholar)γ-Secretase inhibitorsSemagacestat (Eli Lilly)≥58.2% 64.6% 100–140 mg≥47–84% newly 100–280 2011 (AD cancer infections.(110Fleisher A.S. Siemers E.R. Becerra Clark C.M. M.R. Galvin J.E. Peskind Quinn J.F. Sherzai Sowell B.B. Thal L.J. Phase gamma-secretase disease.Arch. 65: 1031-1038Crossref (298) Scholar)(111Bateman R.J. Mawuenyega K.G. Wen Browning K.R. Sigurdson W.C. Yarasheski K.E. Friedrich Demattos R.B. May P.C. Paul Holtzman D.M. decreases central nervous system.Ann. 2009; 66: 48-54Crossref Scholar)(112Doody R.S. Iwatsubo Joffe Kieburtz He Sun Sethuraman Mohs Disease Cooperative Steering CommitteeSemagacestat GroupA 3 semagacestat 2013; 369: 341-350Crossref (706) Scholar)Avagacestat (Bristol-Myers Squibb)≥40% 125 2012 AD)Worsens cancers, diarrhea, nausea, vomiting, rash(116Coric Salloway Richter Soininen Thein Shiovitz Pilcher Colby Rollin Dockens Pachai Portelius al.Safety avagacestat 1430-1440Crossref (236) modulatorsRofecoxib (Merck)Not determinedDiscontinued 2004 efficacy, cardiovascular damage(122Reines Block Morris Nessly Lines Norman Baranak Rofecoxib: No 1-year, randomized, blinded, study.Neurology. 62: 66-71Crossref Scholar)Tarenflurbil (Myriad Genetics)No CSFDiscontinued 2009 dizziness, upper respiratory tract infection constipation.(226Galasko Graff-Radford Cottrell Sagi S.A. Mather Laughlin Zavitz K.H. Swabb Murphy M.P. Koo E.H. Safety, tolerability, pharmacokinetics, short-term administration R-flurbiprofen elderly individuals.Alzheimer Assoc. 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Open table new tab ADAS-Cog, derived undergoes sequential limited proteolysis catalyzed proteases called "secretases" (Fig. 1A) (25Checler Processing Neurochem. 1995; 1431-1444Crossref nonamyloidogenic pathway, cleavage α-secretase ends up fragments: large secreted N-terminal (sAPPα), p3, domain (AICD) 1A). amyloidogenic followed cleavage. Again, generates (sAPPβ) remaining membrane stub, cleavage, liberating counterpart AICD 1B). Other noncanonical cleavages recently described (26Andrew Kellett K.A. Thinakaran Hooper Greek tragedy: proteolysis.J. Chem. 291: 19235-19244Abstract Among them, ƞ-secretase activity, carried matrix metalloproteinases (MT1-MMP MT5-MMP), cleaves domain, producing (sAPPη) membrane-bound ηCTF. latter subsequently processed α- β-secretase, will generate Anα C83 Anβ 1C) (27Willem Tahirovic Busche Ovsepian S.V. Chafai Kootar Hornburg Evans L.D. Moore Daria Hampel Muller Giudici Nuscher Wenninger-Weinzierl al.eta-Secretase inhibits activity hippocampus.Nature. 526: 443-447Crossref (227) 28Baranger Marchalant Bonnet A.E. Crouzin Carrete Paumier Py N.A. Bernard Bauer Charrat Moschke Seiki Vignes Lichtenthaler S.F. Checler al.MT5-MMP pro-amyloidogenic proteinase promotes transgenic mouse model disease.Cell Life Sci. 73: 217-236Crossref (59) Until 28 identified except Swedish mutation, lying within sequence (www.alzforum.org/mutations). variant (APPswe, KM670/671NL), although located residues upstream, strongly those peptides, boosting 29Citron Teplow D.B. Miller D Johnston Venizelos Excessive -protein peripheral cells mutation.Proc. Natl. Acad. 1994; 91: 11993-11997Crossref All lie close site (the middle part C99), sites, near (N-terminal part), modifying secretases. While knowledge exact still limited, seems (such Leuven (E682K)

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