BIN1 as a risk factor in late-onset Alzheimer's disease
Our lab is interested in characterizing GWAS risk factors BIN1, CLU, and PICALM using an integrated approach that employs iPSCs, other in vitro models, and a variety of mouse models.
A major focus of our current research is to understand how BIN1, the second most common late-onset Alzheimer's disease risk gene, functions as a genetic risk factor. 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. BIN1 is expressed in neurons, oligodendrocytes, and microglia as multiple alternatively spliced isoforms. The challenge is to elucidate the neuronal and glial functions of BIN1 and its association with AD risk. We are using a series of cell-type-specific conditional knockout and transgenic mouse models to study BIN1's role in AD pathophysiology. 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. In another line of investigation, we characterized BIN1 interactions with p140Cap and defined the in vivo BIN1 interactome using a proximity-labeling approach. Ongoing research focuses on microglia-specific functions of BIN1 using conditional knock-out and transgenic models.
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McMillan JD et al. Proteomic characterization of the Alzheimer’s disease risk factor BIN1 interactome. Molecular and Cellular Proteomics, 2025. 24(9):101055. doi: 10.1016/j.mcpro.2025.101055.
Zhao X et al. Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication. Molecular Neurodegeneration, 2025, 20(1):51. doi: 10.1101/2024.08.14.24312009.
Blazier DM et al. A biophysical and molecular characterization of the interaction between the Alzheimer risk factor BIN1 and the neuronal scaffold protein p140Cap. J Biol Chem. 2025. 301(10):110665. doi: 10.1016/j.jbc.2025.110665.
Ponnusamy M et al. Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model. Brain. 2023.146(4):1561-1579. doi:10.1093/brain/awac318.
Sudwarts A et al. BIN1 is a key regulator of proinflammatory and neurodegeneration-related activation in microglia. Mol Neurodegener. 2022 May 7;17(1):33. doi: 10.1186/s13024-022-00535-x.
De Rossi P et al. Neuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation. Cell Rep. 2020 Mar 10;30(10):3520-3535.e7. doi: 10.1016/j.celrep.2020.02.026.
Andrew RJ et al. Reduction of late-onset Alzheimer’s disease risk-factor BIN1 expression does not affect amyloid pathology in a mouse model of Alzheimer’s disease. J. Biol. Chem. 2019. 294(12):4477-4487.
De Rossi P et al. Aberrant accrual of BIN1 near Alzheimer’s disease amyloid deposits in transgenic models. Brain Pathology, 2018. doi: 10.1111/bpa.12687. Full Text
De Rossi P et al. BIN1 localization is distinct from Tau tangles in Alzheimer’s disease. Matters, 2017. Full Text
De Rossi P et al. Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol. Neurodegener. 2016, 11:59. DOI 10.1186/s13024-016-0124-1. Full Text