title: Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase.
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.
authors.affiliation: 1] Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan [2].
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kanatsu
authors.affiliation: 1] Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 113-0033, Japan [3].
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morohashi
authors.affiliation: Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Kuroda
authors.affiliation: Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: 1] Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 113-0033, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
authors.affiliation: 1] Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan [2] Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Tokyo 113-0033, Japan [3] Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004705:Endocytosis / Q000235:genetics / Q000502:physiology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D034041:Monomeric Clathrin Assembly Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D034041:Monomeric Clathrin Assembly Proteins; D053829:Amyloid Precursor Protein Secretases