BIN1 as a risk factor in late-onset Alzheimer's disease
A major focus of our current research is to understand how the second most common late-onset Alzheimer's disease risk gene, namely BIN1, contributes to disease pathophysiology. BIN1 is a member of the BAR (Bin/Amphiphysin/ Rvs) adaptor family proteins that regulate membrane dynamics in various cellular contexts, including endocytosis and membrane remodeling. The BIN1 gene undergoes complex alternative splicing to generate more than 15 isoforms, which differ in tissue distribution, subcellular localization, and function. The challenge is to characterize the neuronal and non-neuronal BIN1 expression and investigate, using a series of conditional knock-out and transgenic mouse models, how BIN1 elevates the risk for AD. Our characterization of neuronal Bin1 cKO mice revealed that BIN1 regulates presynaptic neurotransmitter release and memory consolidation. Neuronal BIN1 also regulates tau pathogenesis in a region-specific manner. Moreover, we observed that microglial BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia. Ongoing research focuses on cell-type-specific functions of BIN1 using conditional knock-out and transgenic models.
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