The developmental effects of sex chromosomes and hormones specify microglial inflammation in Alzheimer's diseaes

性染色体和激素的发育影响明确了阿尔茨海默病中的小胶质细胞炎症

• 批准号: 10370098
• 负责人: ERIN G REED
• 金额: $ 39万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370098
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Biochemical; Biological Factors; Biology; Brain; Cell Differentiation process; Cells; Complement; Dementia; Deposition; Development; Developmental Process; Disease; Disease Outcome; Disease Progression; Estradiol; Feminization; Four Core Genotypes; Gene Expression; Genetic; Germ Cells; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Hormones; Immune; Incidence; Indomethacin; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Longevity; Masculine; Measures; Mediating; Mediator of activation protein; Methodology; Methods; Microglia; Mission; Modeling; Molecular; Morphology; Mus; Neonatal; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Receptors; Onset of illness; Outcome; PTPRC gene; Play; Prevalence; Prevention; Prevention strategy; Probability; Process; Proteins; Public Health; Research; Role; Severity of illness; Sex Chromosomes; Sex Differences; Signal Transduction; Specific qualifier value; Techniques; Testing; United States National Institutes of Health; Woman; age related; base; brain cell; combat; extracellular; immune activation; inflammatory milieu; innovation; insight; mouse model; neurochemistry; neurofilament; neuroinflammation; novel; novel therapeutic intervention; receptor function; reduce symptoms; sex; sexual dimorphism; success; therapeutically effective; therapy development; treatment strategy

PROJECT SUMMARY/ABSTRACT Although women are known to be disproportionally affected by Alzheimer’s disease (AD), the underlying biology for this difference is unresolved. Our long-term goal is to help develop therapies that can be used in the prevention and treatment of Alzheimer’s disease and other dementias where inflammation plays a critical role. The overall objectives in this application are to (i) define the mechanisms that specify the inflammatory response in the AD brain, and (ii) elucidate whether these are altered in the presence of circulating hormones. Our central hypothesis is that sex differences in the brain’s immune cells are driven by sex chromosomes and gonadal steroid hormones, resulting in divergent inflammatory processes and therefore AD onset and progression. The rationale for this project is that determining how genetic and hormonal mediators contribute to sex differences in the neuroinflammatory processes in AD will provide a strong scientific framework whereby new therapeutic strategies can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the contribution of sex chromosomes to the inflammatory environment of the AD brain; and 2) Determine the organizational effects of sex hormones in establishing the inflammatory response in the AD brain. Under the first aim, the 5xFAD mouse model of AD will be combined with the Four Core Genotype (FCG) mouse to separate chromosomal and gonadal sex in the context of AD. Inflammation will be assessed using biochemical and molecular techniques to examine immune cell activation and neuronal health and survival. For the second aim, the brains of 5xFAD mice will be masculinized or feminized neonatally to ascertain the effects of gonadal hormones on inflammatory processes. The innovation of this project lies in: 1) the aspects of sex not previously considered in AD models, 2) the contribution of cell differentiation during development to AD risk in ways not previously considered, and 3) the use of methodologies to shift the disease paradigm away from protein functional differences towards expression differences. Providing critical insights to the mechanisms giving rise to immune dysregulation and neuroinflammation in AD are significant because they have the potential to become the basis for new therapeutic strategies.

项目概要/摘要 尽管众所周知，女性尤其容易受到阿尔茨海默病 (AD) 的影响，但 这种差异的潜在生物学原理尚未解决。我们的长期目标是帮助开发可以 用于预防和治疗阿尔茨海默病和其他由炎症引起的痴呆症 关键作用。该应用程序的总体目标是 (i) 定义指定的机制 AD 大脑中的炎症反应，以及 (ii) 阐明这些反应是否在存在以下物质的情况下发生改变： 循环激素。我们的中心假设是，大脑免疫细胞的性别差异是由以下因素驱动的： 性染色体和性腺类固醇激素，导致不同的炎症过程，因此 AD 的发病和进展。该项目的基本原理是确定遗传和荷尔蒙如何影响 介导AD神经炎症过程中性别差异的介质将提供强有力的 可以开发新的治疗策略的科学框架。中心假设将是 通过追求两个特定目标进行测试：1）确定性染色体对炎症的贡献 AD大脑的环境； 2) 确定性激素在建立组织中的作用 AD 大脑中的炎症反应。第一个目标下，将结合AD的5xFAD小鼠模型 使用四核心基因型 (FCG) 小鼠来区分 AD 背景下的染色体和性腺性别。 将使用生化和分子技术来评估炎症，以检查免疫细胞的激活 以及神经元的健康和存活。对于第二个目标，5xFAD 小鼠的大脑将被男性化或 新生儿女性化以确定性腺激素对炎症过程的影响。创新 该项目的重点在于：1）AD模型中以前没有考虑到的性别方面，2）细胞的贡献 在开发过程中以以前未考虑过的方式区分 AD 风险，以及 3) 使用 将疾病范式从蛋白质功能差异转向表达的方法 差异。提供对引起免疫失调和免疫失调的机制的重要见解 AD 中的神经炎症非常重要，因为它们有可能成为新的基础 治疗策略。