The inactive X: discovering sex genes that influence female vulnerability to Alzheimer's disease

项目总结 在定义阿尔茨海默病(AD)的两种标志性蛋白质病--b-淀粉样蛋白和tau蛋白中，研究 一如既往地表明，女性的tau水平高于男性。这一发现在更老的人身上表现得很好 女性，即使是那些临床上被认为是正常的，但驱动这种性行为的生物机制 分歧仍然难以捉摸。由于更年期或激素治疗引起的性激素变化可能是一种 促成因素，尽管影响是模棱两可的。性激素不是唯一的性生理成分 这可能会起到一定作用。性染色体构成了女性生理上的遗传基础 区别于男性。特别是在AD领域，X染色体在很大程度上被忽视了，因为 涉及测量和分析的复杂性。女性拥有两条X染色体，这具有深远的意义 神经退行性疾病与特定性别的关联的含义。为了避免女性服用过量的药物 X连锁基因来自两个X染色体，其中一个X在全身每个细胞中随机沉默。 然而，这种随机的X失活是不完整的，一些基因逃脱了这种失活。在人类中 在女性中，大约30%的X连锁基因在所有组织类型中都能持续逃脱失活。在那些人中 失活X逃逸了文献中已报道的基因(n=60)，许多与免疫有关 系统。由于这种现象，女性往往表现出更强大的免疫系统，更有可能 患有自身免疫性疾病。与AD相关的神经炎症，因强大的免疫而加剧 反应，被认为是脆弱大脑区域病理的关键早期驱动因素。这些关键部分 证据引发了一个从未解决过的创新问题：不活跃的X逃逸基因可能是 解释女性对AD病理易感性的关键是什么？这种机制能否通过一种 炎症途径？因此，在这项创新的提案中，我提出了一种概念上新颖的方法来 通过关注“排除的”染色体来解决AD病理中的性别差异。与 AD遗传学领域的专家同事们，我将利用最新的技术来检测基因组， 体内作为性别差异驱动因素的Inactive-X逃逸基因的转录和表观遗传学影响 B-淀粉样蛋白和tau蛋白的神经影像标志物。这项研究的范围将是无与伦比的，因为我将利用我的 具备神经成像、数据协调和统计学方面的技能，以结合三个大型、表型较深的队列 有b-淀粉样蛋白和tau正电子发射断层扫描，神经成像和全基因组和 转录组测序(n=900)与血液中的促炎标志物：哈佛大学老年脑研究 (HABS)，无症状阿尔茨海默病的抗淀粉样蛋白治疗(A4)研究和纵向评价 淀粉样蛋白风险和神经退行性变(学习)研究。我也会在宗教修道会上证实我的发现 研究、记忆和衰老项目(ROS/MAP)和阿尔茨海默病神经成像倡议(ADNI)。 阐明AD风险的性别特异性机制对确定药物靶点具有深远的影响， 而且在临床试验中还能更好地预测男性和女性的药物反应结果。

PROJECT SUMMARY Of the two hallmark proteinopathies, b-amyloid and tau, that define Alzheimer’s disease (AD), studies consistently show that women exhibit higher levels of tau than men. This finding is well-characterized in older women, even those who are considered clinically normal, but the biological mechanism driving this sex difference remains elusive. Sex hormonal changes, either due to menopause or hormone therapy, may be a contributing factor, although effects are equivocal. Sex hormones are not the only sex biological component that could play a role. Sex chromosomes form the genetic foundation by which women are biologically differentiated from men. The X chromosome, in particular, has largely been ignored in the AD field, due to complexities involving measurement and analysis. Women possess two X chromosomes, which has profound implications for sex-specific associations with neurodegenerative disease. To avoid ‘overdosing’ women with X-linked genes coming from two X chromosomes, one X is randomly silenced in each cell throughout the body. This random X inactivation, however, is incomplete, with some genes escaping this inactivation. In human women, approximately 30% of X-linked genes consistently escape inactivation across all tissue types. Of those inactive X escaped genes that have been reported in the literature (n=60), many are involved in the immune system. Due to this phenomenon, women tend to exhibit more robust immune systems and are more likely to suffer from autoimmune diseases. Of relevance to AD, neuroinflammation, exacerbated by robust immune responses, is argued to be a key early driver of pathology in vulnerable brain regions. These key pieces of evidence give rise to an innovative question that has never been tackled: could inactive X escaped genes be the key to explaining female vulnerability to AD pathology? And could this mechanism occur via an inflammatory pathway? As such, in this innovative proposal I put forward a conceptually novel approach to addressing sex differences in AD pathology by focusing on the ‘eXcluded’ chromosome. In collaboration with expert colleagues in the field of AD genetics, I will employ the latest techniques to examine the genomic, transcriptomic, and epigenetic impact of inactive-X escaped genes as a driver of sex differences in in vivo neuroimaging markers of b-amyloid and tau. This study will be unparalleled in its scope, as I will leverage my skills in neuroimaging, data harmonization and statistics to combine three large, deeply-phenotyped cohorts that have b-amyloid and tau positron emission tomography neuroimaging and samples for whole genome and transcriptome sequencing (n=900) and pro-inflammatory markers in blood: the Harvard Aging Brain Study (HABS), the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. I will also validate my findings in the Religious Orders Study, the Memory and Aging Project (ROS/MAP) and the Alzheimer’s disease Neuroimaging Initiative (ADNI). Elucidating sex-specific mechanisms for AD risk has far-reaching consequences for identifying drug targets, but also better predicting drug response outcomes in men and women in clinical trials.