2. Academic Validation
  3. BIN1 regulates BACE1 intracellular trafficking and amyloid-β production

BIN1 regulates BACE1 intracellular trafficking and amyloid-β production

  • Hum Mol Genet. 2016 Jul 15;25(14):2948-2958. doi: 10.1093/hmg/ddw146.
Toji Miyagawa 1 2,  Ihori Ebinuma 1,  Yuichi Morohashi 1,  Yukiko Hori 1,  Mee Young Chang 3,  Haruhiko Hattori 4,  Tomoaki Maehara 4,  Satoshi Yokoshima 4,  Tohru Fukuyama 4,  Shoji Tsuji 5,  Takeshi Iwatsubo 6,  George C Prendergast 3,  Taisuke Tomita 1
Affiliations

Affiliations

  • 1 Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences taisuke@mol.f.u-tokyo.ac.jp.
  • 2 Department of Neurology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan.
  • 3 Lankenau Institute for Medical Research, PA 19096, USA taisuke@mol.f.u-tokyo.ac.jp.
  • 4 Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya University, 464-8601 Japan taisuke@mol.f.u-tokyo.ac.jp.
  • 5 Department of Neurology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan taisuke@mol.f.u-tokyo.ac.jp.
  • 6 Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, 113-0033 Japan taisuke@mol.f.u-tokyo.ac.jp.
PMID: 27179792 DOI: 10.1093/hmg/ddw146
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.

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