BIN1 regulates BACE1 intracellular trafficking and amyloid-β production

Toji Miyagawa; Ihori Ebinuma; Yuichi Morohashi; Yukiko Hori; Mee Young Chang; Haruhiko Hattori; Tomoaki Maehara; Satoshi Yokoshima; Tohru Fukuyama; Shoji Tsuji; Takeshi Iwatsubo; George C Prendergast; Taisuke Tomita

doi:10.1093/hmg/ddw146

BIN1 regulates BACE1 intracellular trafficking and amyloid-β production

Hum Mol Genet. 2016 Jul 15;25(14):2948-2958. doi: 10.1093/hmg/ddw146. Epub 2016 May 14.

Authors

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Alzheimer Disease / genetics*
Alzheimer Disease / metabolism
Alzheimer Disease / pathology
Amyloid Precursor Protein Secretases / genetics*
Amyloid Precursor Protein Secretases / metabolism
Amyloid beta-Peptides / biosynthesis
Amyloid beta-Peptides / genetics*
Animals
Aspartic Acid Endopeptidases / genetics*
Aspartic Acid Endopeptidases / metabolism
Brain / metabolism
Brain / pathology
Endocytosis / genetics
Endosomes / metabolism
Humans
Lysosomes / metabolism
Mice
Mice, Knockout
Neurons / metabolism
Neurons / pathology
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein Transport
Proteolysis
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism

Substances

Adaptor Proteins, Signal Transducing
Amyloid beta-Peptides
BIN1 protein, human
Nuclear Proteins
Tumor Suppressor Proteins
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human