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    Evidence for and against a pathogenic role for reduced γ-secretase activity in familial Alzheimer’s disease

    238968_238968.pdf (494.0Kb)
    Access Status
    Open access
    Authors
    Verdile, Giuseppe
    Jayne, T.
    Newman, M.
    Sutherland, G.
    Munch, G.
    Musgrave, I.
    Moussavi Nik, H.
    Lardelli, M.
    Date
    2016
    Type
    Journal Article
    
    Metadata
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    Citation
    Verdile, G. and Jayne, T. and Newman, M. and Sutherland, G. and Munch, G. and Musgrave, I. and Moussavi Nik, H. et al. 2016. Evidence for and against a pathogenic role for reduced γ-secretase activity in familial Alzheimer’s disease. Journal of Alzheimer's Disease. 52 (3): pp. 781-799.
    Source Title
    Journal of Alzheimer's Disease
    DOI
    10.3233/JAD-151186
    ISSN
    1387-2877
    School
    School of Biomedical Sciences
    Remarks

    This open access article is distributed under the Creative Commons license http://creativecommons.org/licenses/by-nc/4.0/

    URI
    http://hdl.handle.net/20.500.11937/32300
    Collection
    • Curtin Research Publications
    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 (A βPP/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 A βPP ) 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.

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