title: Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease.
abstract: The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity.
authors.affiliation: Alzheimer's Disease Genetics Laboratory, Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide SA, Australia.
authors.forename: Tanya
authors.initials: T
authors.lastname: Jayne
authors.affiliation: Alzheimer's Disease Genetics Laboratory, Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide SA, Australia.
authors.forename: Morgan
authors.initials: M
authors.lastname: Newman
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute - Biosciences, Faculty of Health Sciences, Curtin University, Kent Street, Bentley, WA, Australia.|School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA, Australia.|McCusker Alzheimer's Disease Research Foundation, Hollywood Private Hospital, Hollywood Medical Centre, Nedlands, WA, Australia.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Verdile
authors.affiliation: Discipline of Pathology, Charles Perkins Centre, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Sutherland
authors.affiliation: Molecular Medicine Research Group & School of Medicine, Western Sydney University, Campbelltown NSW, Australia.
authors.forename: Gerald
authors.initials: G
authors.lastname: Münch
authors.affiliation: Discipline of Pharmacology, School of Medicine, University of Adelaide, North Terrace, Adelaide, SA, Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Musgrave
authors.affiliation: Alzheimer's Disease Genetics Laboratory, Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide SA, Australia.
authors.forename: Seyyed Hani
authors.initials: SH
authors.lastname: Moussavi Nik
authors.affiliation: Alzheimer's Disease Genetics Laboratory, Centre for Molecular Pathology, School of Biological Sciences, University of Adelaide, North Terrace, Adelaide SA, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Lardelli
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D009154:Mutation / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: Amyloid precursor protein secretases; familial Alzheimer’s disease; gamma-secretase; human APP protein; human PSEN1 protein; human PSEN2 protein