title: BIN1 regulates BACE1 intracellular trafficking and amyloid-β production.
abstract: BIN1 is a genetic risk factor of late-onset Alzheimer disease (AD), which was identified in multiple genome-wide association studies. BIN1 is a member of the amphiphysin family of proteins, and contains N-terminal Bin-Amphiphysin-Rvs and C-terminal Src homology 3 domains. BIN1 is widely expressed in the mouse and human brains, and has been reported to function in the endocytosis and the endosomal sorting of membrane proteins. BACE1 is a type 1 transmembrane aspartyl protease expressed predominantly in neurons of the brain and responsible for the production of amyloid-β peptide (Aβ). Here we report that the depletion of BIN1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces BACE1 lysosomal degradation, resulting in increased Aβ production. Our findings provide a mechanistic role of BIN1 in the pathogenesis of AD as a novel genetic regulator of BACE1 levels and Aβ production.
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.|Department of Neurology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan.
authors.forename: Toji
authors.initials: T
authors.lastname: Miyagawa
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Ihori
authors.initials: I
authors.lastname: Ebinuma
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Morohashi
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Lankenau Institute for Medical Research, PA 19096, USA taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Mee
authors.initials: M
authors.lastname: Young Chang
authors.affiliation: Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, 464-8601 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Hattori
authors.affiliation: Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, 464-8601 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Maehara
authors.affiliation: Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, 464-8601 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoshima
authors.affiliation: Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, 464-8601 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukuyama
authors.affiliation: Department of Neurology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.affiliation: Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.affiliation: Lankenau Institute for Medical Research, PA 19096, USA taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.affiliation: Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Tomita
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004705:Endocytosis / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; C101410:BIN1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human