Microglial Activation and Inflammatory Endophenotypes Underlying Sex Differences of Alzheimer’s Disease - PROJECT SUMMARY Alzheimer’s disease (AD) is sexually dimorphic in its prevalence, incidence, symptomology, and neuropathology, but the mechanisms underlying these sex differences are not well understood. While sex differences in susceptibility to inflammation and AD progression have been reported, the relationship between neuro and systemic inflammation and sex differences remains understudied. Our preliminary single-nucleus genomic analyses have identified sex-specific microglial gene signatures in AD patient brains. Single-cell transcriptomic data analysis of human peripheral blood mononuclear cells (PBMCs) implies that multiple sex-specific, candidate pro-inflammatory genes highly overexpressed in myeloid-derived suppressor cells (MDSCs) and other immune cell types in AD. We therefore posit that an interplay between microglia and systematic inflammatory mechanisms (termed the “Microglial activation and inflammatory endophenotypes”) exists and that understanding this system will be essential to improve the mechanistic elucidation of AD pathogenesis and therapeutic development in a sex-specific manner. Recent advances of multimodal single-cell genomic and epigenomic analyses have shed insights into a comprehensive understanding of the neuro-immune and peripheral immune systems underlying sex differences in AD. Integration of the single-cell transcriptome, epigenome, the human interactome, along with large-scale AD genetic loci and functional genomic data from existing diverse AD cohorts are essential for such identification. To address this hypothesis, our short-term goal is to identify next-generation immune modulators for AD sex differences and molecularly targeted treatment development in both male and female patients with AD. We will leverage large-scale single-cell genomic and epigenomic data generated from human brains and bloods with varying degrees of AD pathology available at our National Institute of Aging (NIA)-funded Alzheimer's Disease Research Centers (ADRCs). Aim 1 will test the hypothesis that microglial activation and central neuro-immune transcriptional networks mediate sex differences in AD using single-nucleus genomic (snRNA-seq) and epigenomic (snATAC-seq) analyses of human frozen brain tissues. In parallel, we will utilize network-based, integrative analyses of snRNA-seq and snATAC-seq data from human frozen brains and large-scale genetic and functional genomic data from existing AD cohorts with diverse population to identify glial cell type-specific promoters and enhancers that encode sex-specific master gene regulatory networks for AD. Aim 2 will test the hypothesis that cell type-specific peripheral immune signatures and interactome network changes in AD pathogenesis and progression act in a sex-specific manner. In summary, our project will identify clinically actionable immune molecular mechanisms underlying sex differences in AD pathobiology from the central neuro-immune and peripheral immune systems. The successful completion of this project will advance the understanding of sex difference in AD and serve as the foundation for future translational studies to inform the development of precision medicine in a sex-specific manner.
