Contribution of AD genetic risk and microglial BIN1 to tauopathy

Summary/Abstract Late-onset idiopathic Alzheimer’s Disease (AD) is the most common cause of dementia and the sixth leading cause of death in the United States. While the pathology and disease progression of AD is well-documented, current effective therapies are limited. With the incidence of AD expected to climb over the next half century, it is critical to further investigate the molecular and cellular mechanisms underlying idiopathic AD. Genome-wide association studies have identified numerous noncoding genetic variants that are highly associated with AD, but the cell type specific function of these variants and how they confer AD risk remains unknown. The strongest noncoding risk loci associated with late-onset idiopathic AD is upstream of the gene Bridging Integrator 1 (BIN1). Despite its predicted importance, little is known about how BIN1 is regulated, its cell type specific function or its role in AD pathogenesis. We have previously published that the putative causal single nucleotide risk variant upstream of BIN1 lies within a microglia specific DNA regulatory region, or enhancer. The central hypothesis of this proposal is that BIN1 regulatory risk genetics confer AD risk through a cell type specific and environmental context dependent effect in microglia, with BIN1 expression being regulated by genetic variation within a microglial specific enhancer. We developed novel CRISPR/cas9 mediated enhancer deletions that have led to our strong preliminary data identifying neurodegenerative stimuli specific microglial dysfunction with reduced BIN1 expression secondary to the enhancer deletion. Here we apply innovative in vitro and in vivo methods to ascertain the contribution of human microglial BIN1 to tauopathy. The project goal is to identify the downstream pathways and mediators of microglial BIN1 and intersect with the potential contribution to neuropathology in neurodegeneration (Aim 1), together with the effect of reduced microglial BIN1 expression on the onset and progression of tauopathy in organoids and cocultures (Aim 2) and finally using a xenotransplantation model we developed to identify the role of microglial BIN1 in vivo in a murine model of tauopathy (Aim 3). Together these aims will integrate iPSC modeling, complex cocultures, tauopathy, and xenotransplantation as well as cutting- edge transcriptome and epigenetic methodologies to link human genetic variants in enhancers to microglia gene expression in a humanized mouse model of tauopathy. The long-term goal of this proposal is to elucidate the cells specific roles of non-coding variants in AD pathogenesis to identify novel therapeutic targets and pathways amenable to early intervention and AD prevention.