Mechanisms of X-Chromosome-dependent Sex Difference inAlzheimers Disease

阿尔茨海默病 X 染色体依赖性性别差异的机制

• 批准号: 10033567
• 负责人: Dena Bou Dubal
• 金额: $ 226.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10033567
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Biological; Biological Markers; Biology; Brain; Cell model; Cells; Cessation of life; Classification; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Development; Disease; Dose; Environment; Female; Genes; Genetic Models; Genetic Variation; Grant; Heterogeneity; Hippocampus (Brain); Human; Image; Impaired cognition; In Vitro; Incidence; Individual; Link; Longevity; Measures; Mediating; Molecular; Mus; Nerve Degeneration; Neurons; Nuclear; Pathogenicity; Pathology; Pathway interactions; Play; Population; Proteins; Proxy; Risk; Risk Factors; Role; Sex Chromosomes; Sex Differences; Source; Structure; Synapses; Synaptic plasticity; Testing; Toxic effect; Variant; Woman; X Chromosome; X Inactivation; Y Chromosome; arm; base; biological sex; brain health; cell type; experience; gender expression; gene product; genetic variant; gonad development; in vivo; innovation; lifetime risk; loss of function; loss of function mutation; male; men; mortality; mouse model; relating to nervous system; resilience; sex

PROJECT SUMMARY/ABSTRACT Biologic sex influences Alzheimer's disease (AD) and whether sex chromosomes play a role is unknown. This grant focuses on X-chromosome-derived mechanisms of sex difference that contribute to AD by integrating mouse model and human studies. Understanding this largely unstudied area may reveal new X-based pathways that could ultimately benefit both sexes. Sex differences in AD reveal differing vulnerabilities in men and women. In brief, male sex is a risk factor for rapid progression to death in AD and other neurodegenerative conditions. These findings support the fact that many more women have AD, due in part to their longevity and also to their increased risk or incidence in older age – which together contributes to a higher lifetime risk of AD in women. One major source of biologic difference between the sexes is that females have two X chromosomes and males have one. Using genetic models of sex biology that dissect effects of gonadal development, sex chromosomes, and X and Y chromosome dose, we found that the second X chromosome counters mortality, deficits and toxicity related to hAPP/Aβ in both male and female mice and primary neurons, without altering levels of Aβ or co-pathogenic proteins. Since one X inactivates in females, X dose is largely similar between the sexes. This raises a key question: why would having two X's confer advantage to AD-related measures? While X chromosome inactivation (XCI) silences one X chromosome in XX cells, a small subset of X-linked genes escape XCI. Of these, Kdm6a (Utx), a H3K27-demethylase, robustly and consistently escapes in both mice and humans, causes cognitive deficits in humans with loss of function mutations, and plays a post-developmental role in synaptic plasticity and cognition. In further studies we identified that a second X chromosome confers resilience to AD-related deficits, in part, through increasing Kdm6a. Furthermore, the X chromosome escapee KDM6A may be relevant to human brain health since a genetic variant links to increased expression of its gene product – and that variant assocaties with slower cognitive decline in a population of individuals transitioning to AD. We hypothesize that the X chromosome escapee Kdm6a contributes sex difference and confers resilience to AD and AD-related measures. Specifically, we will test how Kdm6a causes resilience – and probe its molecular pathways. The complimentary clinical arm of this proposal enables us to examine key associations of KDM6A in sex differences of human populations of aging and AD with existing cognitive and biomarker data. Answers to our questions in mice and humans will fundamentally advance mechanistic understanding of sex-based heterogeneity of AD, and will likely pave X-based paths toward urgently needed treatments in AD, personalized for men, women, or both.

项目总结/摘要 生物性别影响阿尔茨海默病（AD），性染色体是否起作用尚不清楚。这 格兰特专注于X染色体衍生的性别差异机制，通过整合 小鼠模型和人类研究。了解这个基本上未研究的领域可能会揭示新的X-基础途径 最终能让两性都受益AD的性别差异揭示了男性和女性不同的脆弱性。 简而言之，男性是AD和其他神经退行性疾病快速进展至死亡的风险因素。 这些发现支持了更多的女性患有AD的事实，部分原因是她们的长寿，也是因为她们的年龄。 老年人的风险或发病率增加-这共同导致女性AD的终生风险更高。 两性之间生物差异的一个主要来源是女性有两条X染色体，而男性有两条X染色体。 吃一个吧。利用性生物学的遗传模型，剖析性腺发育、性染色体、 以及X和Y染色体剂量，我们发现第二个X染色体计数器死亡率，缺陷和 在雄性和雌性小鼠和原代神经元中与hAPP/Aβ相关的毒性，而不改变Aβ水平 或共同致病蛋白质。由于一个X在雌性中失活，因此X剂量在两性之间基本相似。这 提出了一个关键问题：为什么有两个X的赋予优势，以广告相关的措施？而X 染色体失活（XCI）使XX细胞中的一条X染色体沉默， XCI其中，Kdm 6a（Utx），一种H3 K27-脱甲基酶，在小鼠和人类中都强烈且一致地逃逸， 导致人类的认知缺陷与功能丧失突变，并发挥后发展的作用， 突触可塑性和认知。在进一步的研究中，我们发现第二条X染色体赋予了 对AD相关缺陷的恢复力，部分是通过增加Kdm 6a。此外，X染色体 逃逸的KDM 6A可能与人类大脑健康有关，因为遗传变异与增加的 其基因产物--变异体与个体群体中认知能力下降较慢有关 过渡到AD。我们假设X染色体逃逸基因Kdm 6a导致了性别差异， 赋予抗AD和AD相关措施的弹性。具体来说，我们将测试Kdm 6a如何导致弹性， 探测它的分子路径这项建议的免费临床手臂使我们能够检查关键 KDM 6A在老年人和AD人群性别差异中与现有认知和 生物标记数据。在小鼠和人类身上找到答案将从根本上推进 了解基于性别的AD异质性，并可能为迫切需要的基于X的路径铺平道路。 针对男性、女性或两者的个性化AD治疗。