Sex Differences in Epigenetic Parent-of-X Origin and Alzheimer's Disease

表观遗传 X 父母起源与阿尔茨海默病的性别差异

• 批准号: 10525754
• 负责人: Dena Bou Dubal
• 金额: $ 174.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525754
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Area; Biological; Biology; Buffers; Cell model; Cell physiology; Cells; Cessation of life; Classification; Cognition; Cognitive deficits; Data; Dissection; Dosage Compensation (Genetics); Dose; Engineering; Environment; Epigenetic Process; Female; Functional disorder; Gene Silencing; Genes; Genetic; Genetic Models; Genetic Transcription; Grant; Hippocampus (Brain); Human; Incidence; Inherited; Longevity; Mammals; Measures; Modeling; Molecular; Mosaicism; Mus; Nerve Degeneration; Neurites; Neurons; Parents; Pathology; Pathway interactions; Risk; Risk Factors; Role; Sex Chromosomes; Sex Differences; Source; Toxic effect; Woman; X Chromosome; X Inactivation; Y Chromosome; base; biological sex; cell type; experience; gender expression; gonad development; imprint; lifetime risk; male; men; mortality; mouse model; overexpression; parental role; relating to nervous system; sex; tool

Project Summary/Abstract Biologic sex influences Alzheimer’s disease (AD). A major source of biologic difference between the sexes is that females have two X chromosomes and males have one. The sex-specific role of the X chromosome in influencing AD is largely unknown. This grant focuses on X-chromosome-derived mechanisms of sex difference using mouse models and primary neurons combined with genetic and epigenetic tools for molecular dissection. Understanding this understudied 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. 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. Using genetic models of sex biology, 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. 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? Each female cell harbors two X chromosomes but one is silenced through random X chromosome inactivation (XCI). XCI independently silences one X chromosome in every XX cell to achieve dosage compensation of X expression between male and female cells. Thus, XX females are mosaics with their active X chromosomes being either maternally-derived (Xm) or paternally-derived (Xp), whereas males have a single maternal X (Xm). A potential benefit of having two X’s is that the diverse combination of maternal and paternal X chromosomes (Xm+Xp) could buffer deleterious cellular process related to AD. We hypothesize that Xm contributes functional deficits to AD pathophysiology in males through epigenetic mechanisms – and that mosaicism of the X (Xm+Xp) in females buffers deficits. Since Xm and Xp are genetically identical in our models, any differences between the two are attributed to epigenetics. We will pursue two aims: 1. In Aim 1, we will examine epigenetic, parent-of-X origin and its modulation of neural vulnerability to AD- related deficits in XX compared to XY mice and cells. We hypothesize that the maternal X chromosome worsens neural vulnerability to AD. 2. In Aim 2, we will define how silencing, or imprinting, of the maternal X chromosome impacts each sex in AD-related toxicity. We hypothesize that the maternal X silences select genes in a cell-type specific manner – and this contributes to sex-specific neural vulnerability. Answers to our questions in XX compared to XY mice and cells will fundamentally advance mechanistic understanding of how the X chromosome contributes to sex difference in 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）。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，男性有一条。X染色体的性别特异性作用 对AD的影响在很大程度上是未知的。该基金主要研究X染色体衍生的性别差异机制 使用小鼠模型和原代神经元结合遗传和表观遗传工具进行分子解剖。 了解这一未充分研究的领域可能会揭示新的基于X的途径，最终使双方受益 性别AD的性别差异揭示了男性和女性不同的脆弱性。简而言之，男性性行为是一个风险因素， 导致AD快速发展至死亡这些发现支持了这样一个事实，即更多的女性患有AD， 部分原因是他们的寿命，也是他们在老年时的风险或发病率增加-这两者共同促成了一个 女性AD的终生风险更高。利用性生物学的遗传模型，我们发现第二个X 雄性和雌性小鼠中与hAPP/Aβ相关的染色体计数器死亡率、缺陷和毒性 和初级神经元。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。这就提出 一个关键的问题：为什么有两个X的赋予优势，以广告相关的措施？每一个雌性细胞 两条X染色体，但其中一条通过随机X染色体失活（XCI）沉默。XCI独立地 在每个XX细胞中沉默一条X染色体，以实现雄性之间X表达的剂量补偿， 女性细胞因此，XX女性是嵌合体，她们的活性X染色体要么来自母体， (Xm)或父源性（Xp），而雄性具有单个母体X（Xm）。一个潜在的好处是有两个 X染色体的差异性在于父、母X染色体（Xm+Xp）的多样性组合可以缓冲有害的 与AD相关的细胞过程。我们假设Xm有助于AD的功能缺陷 通过表观遗传机制在男性中的病理生理学-以及X（Xm+Xp）在 女性缓冲赤字。由于在我们的模型中Xm和Xp在遗传上是相同的，因此， 两个归因于表观遗传学。我们将追求两个目标： 1.在目标1中，我们将研究表观遗传，父母的X起源及其调制的神经脆弱性，以AD。 与XY小鼠和细胞相比，XX的相关缺陷。我们假设母亲的X染色体 神经系统对AD的脆弱性。 2.在目标2中，我们将定义母亲X染色体的沉默或印记如何影响每个性别， AD相关毒性。我们假设母体X沉默选择细胞类型特异性基因 方式-这有助于性别特异性神经脆弱性。 与XY小鼠和细胞相比，在XX中回答我们的问题将从根本上推进机制 了解X染色体如何影响AD的性别差异，并可能铺平基于X的道路 针对男性、女性或两者的个性化AD急需治疗。

项目成果

X Chromosome Factor Kdm6a Enhances Cognition Independent of Its Demethylase Function in the Aging XY Male Brain.

X 染色体因子 Kdm6a 增强认知能力，独立于其在衰老 XY 男性大脑中的去甲基化酶功能。

• DOI: 10.1093/gerona/glad007
• 发表时间: 2023
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Shaw,CayceK;Abdulai-Saiku,Samira;Marino,Francesca;Wang,Dan;Davis,EmilyJ;Panning,Barbara;Dubal,DenaB
• 通讯作者: Dubal,DenaB