Microglial Activation and Inflammatory Endophenotypes Underlying Sex Differences of Alzheimer’s Disease

项目摘要 阿尔茨海默病（AD）在其患病率、发病率、病理学和神经病理学方面具有性别二态性， 但这些性别差异背后的机制尚不清楚。虽然性别差异在 已经报道了对炎症和AD进展的易感性，神经和 全身性炎症和性别差异仍然研究不足。我们初步的单核基因组 分析已经鉴定了AD患者脑中的性别特异性小胶质细胞基因特征。单细胞转录组 对人外周血单核细胞（PBMC）的数据分析表明，多个性别特异性的、候选的 在骨髓源性抑制细胞（MDSC）和其他免疫细胞中高度过表达的促炎基因， 细胞类型AD。因此，我们认为小胶质细胞和系统性炎症之间的相互作用 机制（称为“小胶质细胞活化和炎症内表型”）的存在， 理解这一系统对于改善AD发病机制的机制阐明是至关重要的， 以性别特异性的方式进行治疗开发。多模式单细胞基因组和 表观基因组学分析为全面了解神经免疫和 外周免疫系统在AD中的性别差异。单细胞转录组的整合， 表观基因组，人类相互作用组，沿着大规模AD遗传基因座和功能基因组数据， 现有的各种AD队列对于这种识别是必不可少的。为了解决这个假设，我们的短期目标是 是识别下一代AD性别差异的免疫调节剂和分子靶向治疗 在男性和女性AD患者中的发展。我们将利用大规模的单细胞基因组和 从具有不同程度AD病理学的人脑和血液产生的表观基因组数据可在 我们的国家老龄化研究所（NIA）资助的阿尔茨海默病研究中心（ADRC）。目标1将测试 小胶质细胞激活和中枢神经免疫转录网络介导性别差异假说 在AD中，使用人冷冻的单核基因组（snRNA-seq）和表观基因组（snATAC-seq）分析， 脑组织同时，我们将利用基于网络的snRNA-seq和snATAC-seq数据的综合分析， 来自人类冷冻大脑和来自现有AD队列的大规模遗传和功能基因组数据， 不同群体以鉴定编码性别特异性主基因的神经胶质细胞类型特异性启动子和增强子 AD的基因调控网络。目的2将检验细胞类型特异性外周免疫 AD发病机制和进展中的信号和相互作用组网络变化以性别特异性方式起作用。 总之，我们的项目将确定临床上可操作的免疫分子机制， AD病理生物学与中枢神经免疫和外周免疫系统的差异。成功 本研究之完成，将增进对AD性别差异之了解，并为 未来的转化研究，以性别特异性方式为精准医学的发展提供信息。

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.