Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
2021; Elsevier BV; Volume: 296; Linguagem: Inglês
10.1016/j.jbc.2021.100489
ISSN1083-351X
AutoresFrédéric Checler, Elissa Afram, Raphaëlle Pardossi‐Piquard, Inger Lauritzen,
Tópico(s)Computational Drug Discovery Methods
ResumoGenetic, biochemical, and anatomical grounds led to the proposal of the amyloid cascade hypothesis centered on the accumulation of amyloid beta peptides (Aβ) to explain Alzheimer's disease (AD) etiology. In this context, a bulk of efforts have aimed at developing therapeutic strategies seeking to reduce Aβ levels, either by blocking its production (γ- and β-secretase inhibitors) or by neutralizing it once formed (Aβ-directed immunotherapies). However, so far the vast majority of, if not all, clinical trials based on these strategies have failed, since they have not been able to restore cognitive function in AD patients, and even in many cases, they have worsened the clinical picture. We here propose that AD could be more complex than a simple Aβ-linked pathology and discuss the possibility that a way to reconcile undoubted genetic evidences linking processing of APP to AD and a consistent failure of Aβ-based clinical trials could be to envision the pathological contribution of the direct precursor of Aβ, the β-secretase-derived C-terminal fragment of APP, βCTF, also referred to as C99. In this review, we summarize scientific evidences pointing to C99 as an early contributor to AD and postulate that γ-secretase should be considered as not only an Aβ-generating protease, but also a beneficial C99-inactivating enzyme. In that sense, we discuss the limitations of molecules targeting γ-secretase and propose alternative strategies seeking to reduce C99 levels by other means and notably by enhancing its lysosomal degradation. Genetic, biochemical, and anatomical grounds led to the proposal of the amyloid cascade hypothesis centered on the accumulation of amyloid beta peptides (Aβ) to explain Alzheimer's disease (AD) etiology. In this context, a bulk of efforts have aimed at developing therapeutic strategies seeking to reduce Aβ levels, either by blocking its production (γ- and β-secretase inhibitors) or by neutralizing it once formed (Aβ-directed immunotherapies). However, so far the vast majority of, if not all, clinical trials based on these strategies have failed, since they have not been able to restore cognitive function in AD patients, and even in many cases, they have worsened the clinical picture. We here propose that AD could be more complex than a simple Aβ-linked pathology and discuss the possibility that a way to reconcile undoubted genetic evidences linking processing of APP to AD and a consistent failure of Aβ-based clinical trials could be to envision the pathological contribution of the direct precursor of Aβ, the β-secretase-derived C-terminal fragment of APP, βCTF, also referred to as C99. In this review, we summarize scientific evidences pointing to C99 as an early contributor to AD and postulate that γ-secretase should be considered as not only an Aβ-generating protease, but also a beneficial C99-inactivating enzyme. In that sense, we discuss the limitations of molecules targeting γ-secretase and propose alternative strategies seeking to reduce C99 levels by other means and notably by enhancing its lysosomal degradation. Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disease. After initial clinical characterization, histopathological analysis revealed the presence of two major anatomical lesions signing this pathology: senile plaques that are extracellular protein aggregates and neurofibrillary tangles that are intracellular neuronal lesions (1Calderon-Garciduenas A.L. Duyckaerts C. Alzheimer disease.Handbook Clin. Neurol. 2017; 145: 325-337Crossref PubMed Scopus (0) Google Scholar, 2DeTure M.A. Dickson D.W. The neuropathological diagnosis of Alzheimer's disease.Mol. Neurodegener. 2019; 14: 32Crossref PubMed Scopus (295) Google Scholar, 3Sengoku R. Aging and Alzheimer's disease pathology.Neuropathology. 2020; 40: 22-29Crossref PubMed Scopus (5) Google Scholar). Senile plaques are mainly composed of the small 4 kDa amyloid beta peptide (Aβ) (4Glenner G.G. Wong C.W. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein.BBRC. 1984; 120: 885-890Crossref PubMed Scopus (0) Google Scholar) and neurofibrillary tangles of hyperphosphorylated and cleaved forms of the microtubule-associated protein tau (5Brion J.P. Flament-Durand J. Dustin P. Alzheimer's disease and tau proteins.Lancet. 1986; 2: 1098Abstract PubMed Google Scholar, 6Goedert M. Spillantini M.G. Jakes R. Rutherford D. Crowther R.A. Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer's disease.Neuron. 1989; 3: 519-526Abstract Full Text PDF PubMed Scopus (1679) Google Scholar). The cloning of the Aβ precursor, the β-amyloid precursor protein (APP), in the late 80s was a key step in the understanding of the pathology. APP was found to be localized on chromosome 21 (7Kang J. Lemaire H.-G. Unterbeck A. Salbaum J.M. Masters C.L. Grzeschik K.-H. Multhaup G. Beyreuther K. Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.Nature. 1987; 325: 733-736Crossref PubMed Scopus (3836) Google Scholar), thus explaining the development of early-onset dementia and the presence of senile plaques in Down syndrome patients carrying an extra copy of APP due to a duplication of this chromosome (8Head E. Lott I.T. Down syndrome and beta-amyloid deposition.Curr. Opin. Neurol. 2004; 17: 95-100Crossref PubMed Scopus (0) Google Scholar). Furthermore, the identification of APP mutations responsible for autosomal dominant form of AD (FAD), including the "Dutch" (9Levy E. Carman M.D. Fernandez-Madrid I. Power M.D. Lieberburg I. Van Drinen S.G. Bots G.T.M. Luyenkijk W. Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type.Science. 1990; 248: 1124-1126Crossref PubMed Google Scholar) "London" (10Goate A. Chartier-Harlin M.C. Mullan M. Brown J. Crawford F. Fidami L. Giuffra L. Haynes A. Irving N. James L. Mant R. Newton P. Rooke K. Roques P. Talbot C. et al.Seggregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.Nature. 1991; 349: 704-706Crossref PubMed Scopus (0) Google Scholar) and "Swedish" mutations (11Mullan M. Crawford F. Axelman K. Houlden H. Lilius L. Winblad B. Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of b-amyloid.Nat. Genet. 1992; 1: 345-347Crossref PubMed Scopus (0) Google Scholar), showed that the functional consequences of these mutations were to augment the load of Aβ and/or to shift Aβ production to more aggregating Aβ peptides (12Citron M. Oltersdorf T. Haass C. McConlogue L. Hung A.Y. Seubert P. Vigo-Pelfrey C. Lieberburg I. Selkoe D.J. Mutation of the b-amyloid precursor protein in familial Alzheimer's disease increases b-protein production.Nature. 1992; 360: 672-674Crossref PubMed Scopus (0) Google Scholar, 13Cai X.-D. Golde T.E. Younkin S.G. Release of excess amyloid b protein from a mutant amyloid b protein precursor.Science. 1993; 259: 514-516Crossref PubMed Google Scholar). The role of Aβ in AD etiology was further confirmed by the discovery few years later of the first mutations in presenilins that were found to be involved in Aβ production and, similarly to APP mutations, seemed to exacerbate Aβ accumulation in cells, animal models as well as in AD-affected human brains (14Wolfe M.S. Unraveling the complexity of gamma-secretase.Semin. Cell Dev. Biol. 2020; 105: 3-11Crossref PubMed Scopus (7) Google Scholar, 15Escamilla-Ayala A. Wouters R. Sannerud R. Annaert W. Contribution of the Presenilins in the cell biology, structure and function of gamma-secretase.Semin. Cell Dev. Biol. 2020; 105: 12-26Crossref PubMed Scopus (8) Google Scholar, 16Lleo A. Berezovska O. Growdon J.H. Hyman B.T. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations.Am. J. Geriatr. Psychiatry. 2004; 12: 146-156Abstract Full Text Full Text PDF PubMed Google Scholar). A last, but very important genetic evidence of a key role of Aβ in AD etiology was the recent findings of the Icelandic APP mutation that was shown to be protective by reducing cognitive decline and Aβ load by about 40% (17Jonsson T. Atwal J.K. Steinberg S. Snaedal J. Jonsson P.V. Bjornsson S. Stefansson H. Sulem P. Gudbjartsson D. Maloney J. Hoyte K. Gustafson A. Liu Y. Lu Y. Bhangale T. et al.A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.Nature. 2012; 488: 96-99Crossref PubMed Scopus (763) Google Scholar). Thus, this set of histopathological, genetic, and biochemical data concurred to support the view that Aβ accumulation could be the etiological cause of the pathology, as stated in the amyloid cascade hypothesis that was proposed in 1992 by Hardy and Higgings (18Hardy J.A. Higgins G.A. Alzheimer's disease: The amyloid cascade hypothesis.Science. 1992; 256: 184-185Crossref PubMed Google Scholar). Indeed, mutations in three distinct proteins, namely APP, PS1, and PS2, are all responsible for FAD and have in common to modulate both APP processing and Aβ production. In this context, one can understand the huge efforts aimed at determining the mechanisms and enzymes involved in Aβ production and designing potent, specific, and bioavailable inhibitors of these enzymes (19Nie P. Vartak A. Li Y.M. gamma-Secretase inhibitors and modulators: Mechanistic insights into the function and regulation of gamma-Secretase.Semin. Cell Dev. Biol. 2020; 105: 43-53Crossref PubMed Scopus (3) Google Scholar, 20Moussa-Pacha N.M. Abdin S.M. Omar H.A. Alniss H. Al-Tel T.H. BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease.Med. Res. Rev. 2020; 40: 339-384Crossref PubMed Scopus (37) Google Scholar) or Aβ neutralizing antibodies. However, until so far, the outcomes of these Aβ-centered strategies have been extremely disappointing in our quest for meaningful treatments (21Huang Y.M. Shen J. Zhao H.L. Major clinical trials failed the amyloid hypothesis of Alzheimer's disease.J. Am. Geriatr. Soc. 2019; 67: 841-844Crossref PubMed Scopus (13) Google Scholar, 22Panza F. Lozupone M. Logroscino G. Imbimbo B.P. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease.Nat. Rev. Neurol. 2019; 15: 73-88Crossref PubMed Scopus (283) Google Scholar) (Table 1). This has led to question the validity of the amyloid cascade hypothesis (23Herrup K. The case for rejecting the amyloid cascade hypothesis.Nat. Neurosci. 2015; 18: 794-799Crossref PubMed Scopus (410) Google Scholar) or to discuss in a more cautious and balanced manner the ins, outs, and limitations of the procedures of clinical trials (24Haass C. Levin J. [Did Alzheimer research fail entirely? Failure of amyloid-based clinical studies].Der. Nervenarzt. 2019; 90: 884-890Crossref PubMed Scopus (0) Google Scholar). It remains that before "throwing out the baby and the bath water," one should try to reconcile undoubted genetic evidences linking APP processing to AD and failures of Aβ-based clinical trials. In this context, a way to reconcile these observations could be to envisage the possible contribution of other APP-derived fragments distinct from Aβ itself to AD pathology. Indeed, growing evidence proposes that the direct precursor of Aβ (see below), the β-secretase-derived fragment, C99, could be an early and main contributor to AD. Thus, in this review, we address the possibility that the failure of Aβ-centric clinical trials could be explained, at least partly, by their lack of effect on C99. To go further, we describe clues and evidences suggesting that γ-secretase should be considered as a beneficial C99-inactivating enzyme and argument against therapeutic strategies targeting this enzyme. We instead propose alternative strategies seeking to circumvent C99 accumulation, which would then have the advantage to reduce both C99 and Aβ levels.Table 1Principal antiamyloid clinical drugs and strategiesStrategyDrug/specific targetAβ modulation in treated AD patientsFDA statute and participantsSide effects/cognitive readoutReferenceActive immunotherapyAN-1792 (synthetic Aβ42, Janssen)≥ 60–70% Aβ load reduction in the brain (post-mortem immonustaining)Discontinued in 2002 (mild to moderate AD patients)Meningoencephalitis(208Nicoll J.A.R. Wilkinson D. Holmes C. Steart P. Markham H. Weller R.O. Neuropathology of human Alzheimer disease after immunization with amyloid-b peptide: A case report.Nat. Med. 2003; 9: 448-452Crossref PubMed Scopus (0) Google Scholar)(209Holmes C. Boche D. Wilkinson D. Yadegarfar G. Hopkins V. Bayer A. Jones R.W. Bullock R. Love S. Neal J.W. Zotova E. Nicoll J.A. Long-term effects of Abeta42 immunisation in Alzheimer's disease: Follow-up of a randomised, placebo-controlled phase I trial.Lancet. 2008; 372: 216-223Abstract Full Text Full Text PDF PubMed Scopus (1113) Google Scholar)(210Boche D. Donald J. Love S. Harris S. Neal J.W. Holmes C. Nicoll J.A. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease.Acta Neuropathol. 2010; 120: 13-20Crossref PubMed Scopus (0) Google Scholar)CAD106 (multiple copies of Aβ1-6 peptide, Novartis)1.3% Aβ reduction in brain PET scan (florbetapir)2–3-fold increase in plasma Aβ40 at 450 mgDiscontinued in 2019 (asymptomatic carriers of APOE-4)Worsens cognition, headache, nasopharyngitis, pyrexia, hypertension, back pain…(211Vandenberghe R. Riviere M.E. Caputo A. Sovago J. Maguire R.P. Farlow M. Marotta G. Sanchez-Valle R. Scheltens P. Ryan J.M. Graf A. Active Abeta immunotherapy CAD106 in Alzheimer's disease: A phase 2b study.Alzheimers Dement. (N. Y.). 2017; 3: 10-22Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)Passive immunotherapyCrenezumab (monomers, oligomers, and fibrils of Aβ, Roche)≥ 70% Aβ42 increase in CSF at 15 mg/kgPhase II ongoing in asymptomatic carriers of PS mutationsLack of efficacyin mild to moderate AD(212Cummings J.L. Cohen S. van Dyck C.H. Brody M. Curtis C. Cho W. Ward M. Friesenhahn M. Rabe C. Brunstein F. Quartino A. Honigberg L.A. Fuji R.N. Clayton D. Mortensen D. et al.Abby: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease.Neurology. 2018; 90: e1889-e1897Crossref PubMed Scopus (27) Google Scholar)Solanezumab (monomeric and soluble forms of Aβ Eli Lilly)170- and 18-fold increase in plasma Aβ40 and Aβ42 respectively no Aβ modulation in brain PET scan (florbetapir) at 400 mgPhase III ongoing in asymptomatic people who have biomarker evidence of brain amyloid depositionLack of efficacyin mild to moderate ADand in asymptomatic carriers of APP and PS mutations(213Honig L.S. Vellas B. Woodward M. Boada M. Bullock R. Borrie M. Hager K. Andreasen N. Scarpini E. Liu-Seifert H. Case M. Dean R.A. Hake A. Sundell K. Poole Hoffmann V. et al.Trial of solanezumab for mild dementia due to Alzheimer's disease.N. Engl. J. Med. 2018; 378: 321-330Crossref PubMed Scopus (399) Google Scholar)Aducanumab (oligomers, and fibrils of Aβ, Biogen)80% Aβ reduction in brain PET scan (florbetapir) at 10 mg/kgPhase III ongoing in an open-label extension study in mild to moderate AD patientsOne of the two trials (EMERGE) was positive with a significant reduction in cognitive decline in mild to moderate AD a biologics license application was submitted to the FDA for approval on July 2020www.alzforum.org/therapeutics/aducanumabGantenerumab (oligomers, and fibrils of Aβ, Roche)≥ 15%, 35% and 78% Aβ reduction in brain PET scan (florbetapir) at 60, 200 and 1200 mg respectivelyPhase III ongoing in an open-label extension study in mild to moderate AD patients (SCarlet RoAD, Marguerite RoAD, and GRADUATE) and in asymptomatic carriers of APP and PS mutations (Dian-Tu)A directional trend for slower clinical decline in mild to moderate AD(214Ostrowitzki S. Deptula D. Thurfjell L. Barkhof F. Bohrmann B. Brooks D.J. Klunk W.E. Ashford E. Yoo K. Xu Z.X. Loetscher H. Santarelli L. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab.Arch. Neurol. 2012; 69: 198-207Crossref PubMed Scopus (282) Google Scholar)(215Klein G. Delmar P. Voyle N. Rehal S. Hofmann C. Abi-Saab D. Andjelkovic M. Ristic S. Wang G. Bateman R. Kerchner G.A. Baudler M. Fontoura P. Doody R. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer's disease: A PET substudy interim analysis.Alzheimers Res. Ther. 2019; 11: 101Crossref PubMed Scopus (19) Google Scholar)BAN2401 (soluble Aβ protofibrils, Biogen)≥ 120% Aβ40 increase in plasma300 fold Aβ42 increase in CSF93% Aβ reduction in brain PET scan (florbetapir) at 10 mg/kgPhase III ongoing in early symptomatic AD patients (Clarity AD) and in asymptomatic people who have biomarker evidence of brain amyloid deposition (AHEAD 3–45)47% and 30% reduction in cognitive decline as judged by the ADAS-Cog and the ADCOMS respetively(216Logovinsky V. Satlin A. Lai R. Swanson C. Kaplow J. Osswald G. Basun H. Lannfelt L. Safety and tolerability of BAN2401--a clinical study in Alzheimer's disease with a protofibril selective Abeta antibody.Alzheimers Res. Ther. 2016; 8: 14Crossref PubMed Scopus (0) Google Scholar)www.alzforum.org/therapeutics/ban2401β-secretase inhibitorsVerubecestat (MK-8931Merck)≥ 57–84% Aβ reduction in CSF at 12–60 mgDiscontinued in 2018 (prodromal, mild to moderate AD patients)Worsens cognition, anxiety, depression, and sleep problems(217Kennedy M.E. Stamford A.W. Chen X. Cox K. Cumming J.N. Dockendorf M.F. Egan M. Ereshefsky L. Hodgson R.A. Hyde L.A. Jhee S. Kleijn H.J. Kuvelkar R. Li W. Mattson B.A. et al.The BACE1 inhibitor verubecestat (MK-8931) reduces CNS beta-amyloid in animal models and in Alzheimer's disease patients.Sci. Transl. Med. 2016; 8: 363ra150Crossref PubMed Google Scholar)(218Egan M.F. Kost J. Voss T. Mukai Y. Aisen P.S. Cummings J.L. Tariot P.N. Vellas B. van Dyck C.H. Boada M. Zhang Y. Li W. Furtek C. Mahoney E. Harper Mozley L. et al.Randomized trial of verubecestat for prodromal Alzheimer's disease.N. Engl. J. Med. 2019; 380: 1408-1420Crossref PubMed Scopus (196) Google Scholar)Atabecestat (Janssen)≥ 67–90% Aβ reduction in CSF at 10–50 mgDiscontinued in 2018 (asymptomatic people)Worsens cognition, elevated liver enzymes, depression, anxiety, and sleep problems(219Timmers M. Streffer J.R. Russu A. Tominaga Y. Shimizu H. Shiraishi A. Tatikola K. Smekens P. Borjesson-Hanson A. Andreasen N. Matias-Guiu J. Baquero M. Boada M. Tesseur I. Tritsmans L. 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. 2018; 10: 85Crossref PubMed Scopus (0) Google Scholar)(220Henley D. Raghavan N. Sperling R. Aisen P. Raman R. Romano G. Preliminary results of a trial of atabecestat in preclinical Alzheimer's disease.N. Engl. J. Med. 2019; 380: 1483-1485Crossref PubMed Scopus (88) Google Scholar)Lanabecestat (AZD3293,Eli Lilly)≥64% to 78% Aβ reduction in plasma at 15–50 mg≥51% to 76% Aβ reduction in CSF at 15–50 mgDiscontinued in 2018 (prodromal and mild AD patients)Lack of efficacy on cognition, neuropsychiatric adverse events, weight loss, hair color changes(221Cebers G. Alexander R.C. Haeberlein S.B. Han D. Goldwater R. Ereshefsky L. Olsson T. Ye N. Rosen L. Russell M. Maltby J. Eketjall S. Kugler A.R. AZD3293: Pharmacokinetic and pharmacodynamic effects in healthy subjects and patients with Alzheimer's disease.J. Alzheimers Dis. 2017; 55: 1039-1053Crossref PubMed Scopus (48) Google Scholar)(222Wessels A.M. Tariot P.N. Zimmer J.A. Selzler K.J. Bragg S.M. Andersen S.W. Landry J. Krull J.H. Downing A.M. Willis B.A. Shcherbinin S. Mullen J. Barker P. Schumi J. Shering C. 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: 199-209Crossref PubMed Scopus (39) Google Scholar)Umibecestat (Novartis)≥ 90% Aβ reduction in CSF at 85 mgDiscontinued in 2019 (asymptomatic carriers of APOE-4)Worsens cognition, brain atrophy and weight loss(223Neumann U. Ufer M. Jacobson L.H. Rouzade-Dominguez M.L. Huledal G. Kolly C. Luond R.M. Machauer R. Veenstra S.J. Hurth K. Rueeger H. Tintelnot-Blomley M. Staufenbiel M. Shimshek D.R. Perrot L. et al.The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.EMBO Mol. Med. 2018; 10Crossref PubMed Scopus (19) Google Scholar)(187Lopez Lopez C. Tariot P.N. Caputo A. Langbaum J.B. Liu F. Riviere M.E. Langlois C. Rouzade-Dominguez M.L. Zalesak M. Hendrix S. Thomas R.G. Viglietta V. Lenz R. Ryan J.M. Graf A. 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. (N Y). 2019; 5: 216-227Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar) www.alzforum.org/therapeutics/umibecestatElenbecestat (Biogen)≥5.8% and ≥13.6% Aβ reduction in brain PET scan (florbetaben and florbetapir respectively) at 50 mgDiscontinued in 2019 (prodromal, mild to moderate AD patients)Weight loss, skin rashes and neuropsychiatric adverse events(224Lynch S.Y. Kaplow J. Zhao J. Dhadda S. Luthman J. Albala B. Elenbecestat, E2609, 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.Alzheimer's Dement. 2018; 14: P1623Abstract Full Text Full Text PDF PubMed Google Scholar)(225Imbimbo B.P. Watling M. Investigational BACE inhibitors for the treatment of Alzheimer's disease.Expert Opin. Investig. Drugs. 2019; 28: 967-975Crossref PubMed Scopus (36) Google Scholar)γ-Secretase inhibitorsSemagacestat (Eli Lilly)≥58.2% to 64.6% Aβ reduction in plasma at 100–140 mg≥47–84% newly Aβ reduction in CSF at 100–280 mgDiscontinued in 2011 (AD patients)Worsens cognition, skin cancer and infections.(110Fleisher A.S. Raman R. Siemers E.R. Becerra L. Clark C.M. Dean R.A. Farlow M.R. Galvin J.E. Peskind E.R. Quinn J.F. Sherzai A. Sowell B.B. Aisen P.S. Thal L.J. Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease.Arch. Neurol. 2008; 65: 1031-1038Crossref PubMed Scopus (298) Google Scholar)(111Bateman R.J. Siemers E.R. Mawuenyega K.G. Wen G. Browning K.R. Sigurdson W.C. Yarasheski K.E. Friedrich S.W. Demattos R.B. May P.C. Paul S.M. Holtzman D.M. A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.Ann. Neurol. 2009; 66: 48-54Crossref PubMed Scopus (0) Google Scholar)(112Doody R.S. Raman R. Farlow M. Iwatsubo T. Vellas B. Joffe S. Kieburtz K. He F. Sun X. Thomas R.G. Aisen P.S. Siemers E. Sethuraman G. Mohs R. Alzheimer's Disease Cooperative Study Steering CommitteeSemagacestat Study GroupA phase 3 trial of semagacestat for treatment of Alzheimer's disease.N. Engl. J. Med. 2013; 369: 341-350Crossref PubMed Scopus (706) Google Scholar)Avagacestat (Bristol-Myers Squibb)≥40% Aβ reduction in CSF at 125 mgDiscontinued in 2012 (prodromal AD)Worsens cognition, skin cancers, diarrhea, nausea, vomiting, and rash(116Coric V. van Dyck C.H. Salloway S. Andreasen N. Brody M. Richter R.W. Soininen H. Thein S. Shiovitz T. Pilcher G. Colby S. Rollin L. Dockens R. Pachai C. Portelius E. et al.Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease.Arch. Neurol. 2012; 69: 1430-1440Crossref PubMed Scopus (236) Google Scholar)γ-Secretase modulatorsRofecoxib (Merck)Not determinedDiscontinued in 2004 (mild to moderate AD patients)Lack of efficacy, cardiovascular damage(122Reines S. Block G. Morris J. Liu G. Nessly M. Lines C. Norman B. Baranak C. Rofecoxib: No effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study.Neurology. 2004; 62: 66-71Crossref PubMed Google Scholar)Tarenflurbil (Myriad Genetics)No Aβ42 modulation in plasma and CSFDiscontinued in 2009 (mild AD patients)Worsens cognition, dizziness, upper respiratory tract infection and constipation.(226Galasko D.R. Graff-Radford N. May S. Hendrix S. Cottrell B.A. Sagi S.A. Mather G. Laughlin M. Zavitz K.H. Swabb E. Golde T.E. Murphy M.P. Koo E.H. Safety, tolerability, pharmacokinetics, and Abeta levels after short-term administration of R-flurbiprofen in healthy elderly individuals.Alzheimer Dis. Assoc. Disord. 2007; 21: 292-299Crossref PubMed Scopus (0) Google Scholar)(123Green R.C. Schneider L.S. Amato D.A. Beelen A.P. Wilcock G. Swabb E.A. Zavitz K.H. Tarenflurbil Phase 3 Study GroupEffect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: A randomized controlled trial.JAMA. 2009; 302: 2557-2564Crossref PubMed Scopus (476) Google Scholar)Naproxen (Procter & Gamble)No Aβ42 modulations in CSFDiscontinued in 2019 (asymptomatic carriers of APP and PS mutations)Lack of efficacy, hypertension, gastrointestinal, and vascular or cardiac problems(124Meyer P.F. Tremblay-Mercier J. Leoutsakos J. Madjar C. Lafaille-Maignan M.E. Savard M. Rosa-Neto P. Poirier J. Etienne P. Breitner J. Group P.-A.R. INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease.Neurology. 2019; 92: e2070-e2080PubMed Google Scholar)ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCOMS, Alzheimer's Disease Composite Score; CSF, cerebrospinal fluid; FDA, US Food and Drug Administration; MCI, mild cognitive impairment. Open table in a new tab ADAS-Cog, Alzheimer's Disease Assessment Scale-Cognitive Subscale; ADCOMS, Alzheimer's Disease Composite Score; CSF, cerebrospinal fluid; FDA, US Food and Drug Administration; MCI, mild cognitive impairment. Aβ is derived from APP that undergoes sequential limited proteolysis catalyzed by proteases called "secretases" (Fig. 1A) (25Checler F. Processing of the b-amyloid precursor protein and its regulation in Alzheimer's disease.J. Neurochem. 1995; 65: 1431-1444Crossref PubMed Google Scholar). In the nonamyloidogenic pathway, cleavage by α-secretase and γ-secretase ends up with the production of three fragments: a large secreted N-terminal fragment (sAPPα), a small soluble peptide p3, and the APP intracellular domain (AICD) (Fig. 1A). In the amyloidogenic pathway, a first cleavage of APP by the β-secretase is followed by γ-secretase cleavage. Again, the cleavage by β-secretase generates a large soluble extracellular secreted domain (sAPPβ) and the remaining membrane stub, the β-secretase-derived fragment, C99, undergoes γ-secretase cleavage, thus liberating Aβ and its C-terminal counterpart AICD (Fig. 1B). Other noncanonical cleavages on APP have also been more recently described (26Andrew R.J. Kellett K.A. Thinakaran G. Hooper N.M. A Greek tragedy: The growing complexity of Alzheimer amyloid precursor protein proteolysis.J. Biol. Chem. 2016; 291: 19235-19244Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Among them, the ƞ-secretase activity, carried by the matrix metalloproteinases (MT1-MMP and MT5-MMP), cleaves APP in its extracellular domain, thus producing a soluble fragment (sAPPη) and a membrane-bound C-terminal fragment, ηCTF. This latter fragment can subsequently be processed by α- or β-secretase, which will generate Anα and C83 and Anβ and C99, respectively (Fig. 1C) (27Willem M. Tahirovic S. Busche M.A. Ovsepian S.V. Chafai M. Kootar S. Hornburg D. Evans L.D. Moore S. Daria A. Hampel H. Muller V. Giudici C. Nuscher B. Wenninger-Weinzierl A. et al.eta-Secretase processing of APP inhibits neuronal activity in the hippocampus.Nature. 2015; 526: 443-447Crossref PubMed Scopus (227) Google Scholar, 28Baranger K. Marchalant Y. Bonnet A.E. Crouzin N. Carrete A. Paumier J.M. Py N.A. Bernard A. Bauer C. Charrat E. Moschke K. Seiki M. Vignes M. Lichtenthaler S.F. Checler F. et al.MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease.Cell Mol. Life Sci. 2016; 73: 217-236Crossref PubMed Scopus (59) Google Scholar). Until so far, 28 pathogenic APP mutations have been identified with all, except the Swedish mutation, lying within the sequence of C99 (www.alzforum.org/mutations). The Swedish variant (APPswe, KM670/671NL), although not located within C99 but two residues upstream, strongly increases the levels of this fragment, as well as those of Aβ peptides, by boosting β-secretase cleavage (12Citron M. Oltersdorf T. Haass C. McConlogue L. Hung A.Y. Seubert P. Vigo-Pelfrey C. Lieberburg I. Selkoe D.J. Mutation of the b-amyloid precursor protein in familial Alzheimer's disease increases b-protein production.Nature. 1992; 360: 672-674Crossref PubMed Scopus (0) Google Scholar, 13Cai X.-D. Golde T.E. Younkin S.G. Release of excess amyloid b protein from a mutant amyloid b protein precursor.Science. 1993; 259: 514-516Crossref PubMed Google Scholar, 29Citron M. Vigo-Pelfrey C. Teplow D.B. Miller C. D S. Johnston J. Winblad B. Venizelos N. Lannfelt L. Selkoe D.J. Excessive production of amyloid -protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11993-11997Crossref PubMed Scopus (0) Google Scholar). All pathogenic APP mutations lie either close to the α-secretase cleavage site (the middle part of the Aβ domain of C99), within the γ-secretase cleavage sites, or near the β-secretase cleavage site (N-terminal part), thus modifying the cleavages of APP by either of these secretases. While the knowledge about the exact effects of the pathogenic APP mutations is still limited, it seems that mutations close to the β-secretase (such as the Swedish and Leuven (E682K) mutations
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