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Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase

Author

Listed:
  • Kunihiko Kanatsu

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Yuichi Morohashi

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency)

  • Mai Suzuki

    (Graduate School of Humanities and Sciences, Nara Women’s University)

  • Hiromasa Kuroda

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo)

  • Toshio Watanabe

    (Graduate School of Humanities and Sciences, Nara Women’s University)

  • Taisuke Tomita

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency)

  • Takeshi Iwatsubo

    (Graduate School of Pharmaceutical Sciences, The University of Tokyo
    Core Research for Evolutional Science and Technology, Japan Science and Technology Agency
    Graduate School of Medicine, The University of Tokyo)

Abstract

A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (PICALM/CALM) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.

Suggested Citation

  • Kunihiko Kanatsu & Yuichi Morohashi & Mai Suzuki & Hiromasa Kuroda & Toshio Watanabe & Taisuke Tomita & Takeshi Iwatsubo, 2014. "Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase," Nature Communications, Nature, vol. 5(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4386
    DOI: 10.1038/ncomms4386
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