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 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-beta peptide (A beta). Here we report that the depletion of BIN1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces BACE1 lysosomal degradation, resulting in increased A beta production. Our findings provide a mechanistic role of BIN1 in the pathogenesis of AD as a novel genetic regulator of BACE1 levels and A beta production.