Sex chromosomal regulation of hippocampal microglial activation with Alzheimer's disease and aging

摘要 性别和年龄是阿尔茨海默病（AD）的主要风险因素，AD是最常见的痴呆症形式。后 几十年来，治疗阿尔茨海默病（AD）的临床试验失败，迫切需要创造性的 探索新的治疗靶点。虽然女性的患病率更高， 神经病理学和AD的更大认知下降，诊断为AD的男性更快地死亡。 然而，关于驱动性别偏见的机制（无论是激素还是性染色体）知之甚少。 对AD病理学与脑老化的反应。我们的长期目标是确定潜在的机制 对AD的性别偏见反应。最近的GWAS研究已经确定了基因中的几个AD风险位点 专门由小胶质细胞表达，转移领域，探索小胶质细胞在AD中的潜在致病作用。作为 小胶质细胞在衰老和阿尔茨海默病中表现出明显的性别差异。我们假设性 小胶质细胞反应性的差异在机制上有助于性别偏见的疾病进展， AD.虽然AD的发病与女性的绝经过渡期相关，但激素替代疗法 (HRT)结果好坏参半。以前被低估的性染色体的作用， 最近来到AD研究的前沿，特别强调X编码的组蛋白修饰剂。的 本研究的目的是确定性染色体补体（XX v. XY），独立于性激素， 改变AD的病理进展和小胶质细胞激活概况，并检验X编码的 赖氨酸特异性脱甲基酶Kdm 6a有助于对AD的性分化小胶质细胞反应。我们的具体 目的将测试以下假设：（目的1）性染色体补体改变生存和病理 AD的进展（斑块/缠结，小胶质细胞增生）;（目的2）性染色体调节的差异， 小胶质细胞对衰老和AD的异质性反应部分是由组蛋白的改变驱动的， 修饰（H3 K27 me 3）;（目的3）小胶质细胞X编码的Kdm 6a表达足以引起性- 通过全基因组靶向去除抑制性H3 K27 me 3，发散性小胶质细胞对AD的反应。的 在这些研究中产生的配对表型和多组学数据将有助于性别鉴定， 差异调节的基因组程序，赋予保护或风险的进展，AD在两种性别， 以便优先考虑用于AD治疗干预的小分子或表观基因组编辑的靶标。研究 该计划是创新的，因为我们通过性染色体的透镜研究AD的性别差异，并利用 突破性的转录组学、表观基因组学和分析技术， 小胶质细胞异质性的分辨率。

ABSTRACT Sex and age are the primary risk factors for Alzheimer’s disease (AD), the most common form of dementia. After decades of failed clinical trials for the treatment of Alzheimer’s disease (AD), there is an urgent need for creative approaches to uncover new therapeutic targets. While women experience a greater prevalence, more severe neuropathology, and greater cognitive decline with AD, men diagnosed with AD progress more quickly to death. However, little is known about the mechanisms (whether hormonal or sex chromosomal) driving the sex-biased response to AD pathology with brain aging. Our long-term goal is to identify the underlying mechanisms governing the sex-biased response to AD. Recent GWAS studies have identified several AD risk loci in genes exclusively expressed by microglia, shifting the field to explore potential causative roles of microglia in AD. As well, microglia show profound phenotypic sex differences with aging and AD. We hypothesize that sex differences in microglial responsivity contribute mechanistically to the sex-biased disease progression seen in AD. Although the onset of AD correlates to the menopausal transition in women, hormone replacement therapies (HRT) have generated mixed results. The formerly under-appreciated role of sex chromosomal contributions has recently come to the forefront in AD research, with a special emphasis on X-encoded histone modifiers. The objective of this study is to determine if sex chromosome complement (XX v. XY), independent of sex hormones, alters pathological progression and microglial activational profiles in AD and test the hypothesis that X-encoded lysine-specific demethylase Kdm6a contributes to the sexually divergent microglial response to AD. Our specific aims will test the following hypotheses: (Aim 1) sex chromosome complement alters survival and pathological progression (plaques/tangles, microgliosis) of AD; (Aim 2) sex chromosomally regulated differences in heterogeneous microglial cell responses to aging and AD are driven, in part, by alterations in histone modifications (H3K27me3); (Aim 3) microglial X-encoded Kdm6a expression is sufficient to cause sexually- divergent microglial response to AD through genome-wide, targeted removal of repressive H3K27me3. The paired phenotypic and multi-omic data generated in these studies will facilitate the identification of sex- differentially regulated genomic programs that confer protection or risk to the progression of AD in both sexes in order to prioritize targets for small molecule or epigenome editing for therapeutic intervention in AD. The research plan is innovative because we investigate sex differences in AD through the lens of sex chromosomes and utilize ground-breaking transcriptomic, epigenomic, and analytical techniques to gain a previously unattainable resolution of microglia heterogeneity.