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

项目总结 阿尔茨海默病(AD)在患病率、发病率、症状和神经病理学方面具有性别二型性， 但这些性别差异背后的机制还没有被很好地理解。而在性别差异方面 炎症和AD进展的易感性已有报道，神经元和AD进展之间的关系 全身性炎症和性别差异仍未得到充分研究。我们的初步单核基因组 分析已经在AD患者的大脑中发现了性别特异性的小胶质细胞基因特征。单细胞转录 对人类外周血单个核细胞(PBMC)的数据分析表明，多个性别特定、候选 促炎基因在髓系来源的抑制细胞(MDSCs)和其他免疫组织中高表达 AD中的细胞类型。因此，我们假设小胶质细胞和全身炎症之间的相互作用 机制(称为“小胶质细胞激活和炎症内表型”)是存在的，并且 了解这一系统对于提高AD发病机制和机制的阐明具有重要意义。 针对不同性别的治疗进展。多模式单细胞基因组学和分子生物学研究进展 表观基因组学分析为全面理解神经免疫和 阿尔茨海默病性别差异背后的外周免疫系统。单细胞转录组的整合， 表观基因组，人类交互作用组，以及大规模AD遗传基因座和来自 现有不同的AD队列对于这种识别是必不可少的。为了解决这一假设，我们的短期目标是 是确定AD性别差异的下一代免疫调节剂和分子靶向治疗 男性和女性阿尔茨海默病患者的发展。我们将利用大规模的单细胞基因组和 从具有不同程度AD病理的人脑和血液中产生的表观基因组数据可在 我们的国家老龄研究所(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调节性别差异的假说 用冷冻的人单核基因组(SnRNA-Seq)和表观基因组(SnATAC-Seq)分析AD 脑组织。同时，我们将利用基于网络的综合分析SNRNA-SEQ和SNATAC-SEQ数据 来自人类冷冻的大脑，以及来自现有AD队列的大规模遗传和功能基因组数据 识别编码性别特异性主控的胶质细胞类型特异性启动子和增强子的多样化群体 AD的基因调控网络。目标2将检验细胞类型特异性外周免疫的假设 阿尔茨海默病发病和进展过程中的信号和相互作用网络变化以性别特异性的方式起作用。 综上所述，我们的项目将确定性别背后的临床可操作的免疫分子机制。 AD病理生物学与中枢神经免疫系统和外周免疫系统的差异。成功者 该项目的完成将促进对阿尔茨海默病性别差异的了解，并为 未来的翻译研究将以特定性别的方式为精确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.