Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY BIN1, an adaptor protein encoded by the second most common susceptibility GWAS risk factor of late-onset AD, regulates membrane dynamics in the context of endocytosis, membrane remodeling, and synaptic vesicle release. Large-scale expression datasets have reported high-level BIN1 expression in microglia, and AD- associated BIN1 SNPs are thought to alter BIN1 expression through a microglia-specific enhancer. However, the precise functional role(s) of microglial BIN1 in regulating AD pathophysiology has not been investigated systematically. Our central hypothesis is that microglial BIN1 plays an essential role in neuroinflammatory signaling through which BIN1 influences AD pathophysiology. Our preliminary studies show that the loss of Bin1 expression in vitro (cultured microglia) and in vivo (microglia-specific cKO mice) profoundly impairs proinflammatory gene expression and the upregulation of several disease-associated microglia (DAM) genes. Our transcriptomic profiling identified BIN1 as a homeostatic microglial regulator with a non-redundant role in activating proinflammatory response upstream of Apoe, Trem2, and Tyrobp, and upstream of PU.1 and IRF1. BIN1 was predicted to regulate type 1 and 2 interferon responses in microglia in vitro and in vivo. Collectively, these findings offer important insights into microglial BIN1 function, demonstrating its significance in brain inflammatory response. The overall objective of this proposal is to explore BIN1’s role in microglia further, especially in the context of AD pathogenesis, and gain molecular insights. The goal of Aim 1 is to generate 5XFAD:Bin1 cKO mice to elucidate microglial BIN1 function in the modulation of cerebral amyloid burden and amyloid-associated pathophysiology. We will conduct detailed biochemical, molecular, and neuropathological characterization and perform transcriptomics profiling of neuroinflammation and DAM transition to understand BIN1’s role in microglial response to amyloid pathology. Aim 2 studies seek to generate PS19:Bin1 cKO mice to elucidate the involvement of microglial BIN1 function in tau pathophysiology and pathology propagation using detailed neuropathology and comprehensive biochemical, proteomics, and molecular analyses. Aim 3 studies will investigate the mechanistic role of BIN1 as a crucial regulator of early inflammatory signaling events in microglia. We will use unbiased and hypothesis-driven approaches to define the microglial BIN1 interactome and elucidate how BIN1 and its binding partners are reorganized in a context-dependent manner to facilitate immune signaling via key microglial receptors. This timely and unique proposal is highly innovative. Our strategy to use microglia-specific inducible Bin1 cKO mice represents the most direct in vivo approach to rigorously investigate how microglial BIN1 regulates AD pathophysiology and gain insights using comprehensive transcriptomics, proteomics, and interactome characterization. We believe that the successful completion of the proposed research will fill significant gaps in our understanding of BIN1 as a risk factor for LOAD and guide future functional characterizations of molecular pathways and pathogenic mechanisms regulated by this major LOAD risk gene.
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