title: Partial loss of CALM function reduces Aβ42 production and amyloid deposition in vivo.
abstract: Aberrant production, clearance and deposition of amyloid-β protein (Aβ) in the human brain have been implicated in the aetiology of Alzheimer disease (AD). γ-Secretase is the enzyme responsible for generating various Aβ species, such as Aβ40 and toxic Aβ42. Recently, genome-wide association studies in late-onset AD patients have identified the endocytosis-related phosphatidylinositol-binding clathrin assembly protein (PICALM) gene as a genetic risk factor for AD. We previously found that the loss of expression of CALM protein encoded by PICALM affects the ratio of production of Aβ42, through the regulation of the clathrin-mediated endocytosis of γ-secretase. Here, we show that the binding capacity of the assembly protein 180 N-terminal homology (ANTH) domain of CALM to phosphatidylinositol-4,5-biphosphate, as well as to nicastrin, is critical to the modulation of the internalization of γ-secretase and to the Aβ42 production ratio. Moreover, reduction of CALM decreases Aβ deposition as well as brain levels of insoluble Aβ42 in vivo These results suggest that CALM expression modifies AD risk by regulating Aβ pathology.
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Kanatsu
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Takatori
authors.affiliation: Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women's University, Nara, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D034041:Monomeric Clathrin Assembly Proteins / Q000096:biosynthesis / Q000235:genetics*; D009154:Mutation; D010446:Peptide Fragments / Q000235:genetics*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D010446:Peptide Fragments; D019269:Phosphatidylinositol 4,5-Diphosphate; C075222:amyloid beta-protein (1-42); C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases