α-Secretase-Derived Product of β-Amyloid Precursor Protein Is Decreased by Presenilin 1 Mutations Linked to Familial Alzheimer's Disease

Authors

  • Karine Ancolio,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France
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  • Philippe Marambaud,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France
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  • Pascale Dauch,

    1. Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France
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  • Frédéric Checler

    Corresponding author
    1. Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, Sophia Antipolis, Valbonne, France
      Address correspondence and reprint requests to Dr. F. Checler at Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
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Address correspondence and reprint requests to Dr. F. Checler at Institut de Pharmacologie Moléculaire et Cellulaire, UPR 411 du CNRS, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.

Abstract

Abstract: Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familial forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PS1 mutations clearly trigger an increased production of the 42-amino-acid-long species of β-amyloid peptide (Aβ). Here we show that overexpression of wild-type PS1 in HK293 cells increases Aβ40 secretion. By contrast, FAD-linked mutants of PS1 trigger increased secretion of both Aβ40 and Aβ42 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PS1 augments the α-secretase-derived C-terminally truncated fragment of β-amyloid precursor protein (APPα) recovery, whereas transfectants expressing mutated PS1 secrete drastically lower amounts of APPα when compared with cells expressing wild-type PS1. This decrease was also observed when comparing double transfectants overexpressing wild-type β-amyloid precursor protein and either PS1 or its mutated congener M146V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of Aβ42 over total Aβ secretion but concomitantly down-regulate the production of APPα.

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