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Type: Journal article
Title: Evidence for and against a pathogenic role of reduced γ-secretase activity in familial Alzheimer's disease
Other Titles: Evidence for and against a pathogenic role of reduced gamma-secretase activity in familial Alzheimer's disease
Author: Jayne, T.
Newman, M.
Verdile, G.
Sutherland, G.
Münch, G.
Musgrave, I.
Moussavi Nik, S.
Lardelli, M.
Citation: Journal of Alzheimer's Disease, 2016; 52(3):781-799
Publisher: IOS Press
Issue Date: 2016
ISSN: 1387-2877
Statement of
Tanya Jayne, Morgan Newman, Giuseppe Verdile, Greg Sutherland, Gerald Münch, Ian Musgrave, Seyyed Hani Moussavi Nik and Michael Lardelli
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.
Keywords: Amyloid precursor protein secretases; familial Alzheimer’s disease; gamma-secretase; human APP protein; human PSEN1 protein; human PSEN2 protein
Description: Published 23 May 2016
Rights: © 2016 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
RMID: 0030046859
DOI: 10.3233/JAD-151186
Grant ID:
Appears in Collections:Genetics publications

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