BIN1 regulates BACE1 intracellular trafficking and amyloid-β production

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...

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Bibliographic Details
Published in:Human molecular genetics 2016-07, Vol.25 (14), p.2948-2958
Main Authors: Miyagawa, Toji, Ebinuma, Ihori, Morohashi, Yuichi, Hori, Yukiko, Young Chang, Mee, Hattori, Haruhiko, Maehara, Tomoaki, Yokoshima, Satoshi, Fukuyama, Tohru, Tsuji, Shoji, Iwatsubo, Takeshi, Prendergast, George C, Tomita, Taisuke
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Amyloid beta-Peptides - biosynthesis
Amyloid beta-Peptides - genetics
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
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
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Summary: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.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddw146