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

项目摘要/摘要 尽管众所周知，女性受到阿尔茨海默氏症(AD)的影响不成比例，但 造成这种差异的潜在生物学因素尚未解决。我们的长期目标是帮助开发能够 用于预防和治疗阿尔茨海默病和其他炎症起作用的痴呆症 关键角色。本申请的总体目标是(I)定义指定 AD大脑中的炎症反应，以及(Ii)阐明这些反应是否在存在的情况下改变 循环中的荷尔蒙。我们的中心假设是大脑免疫细胞中的性别差异是由 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。这个项目的基本原理是确定基因和荷尔蒙如何 介质的性别差异在AD的神经炎性过程中将提供强有力的 科学框架，据此可以开发新的治疗策略。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性疾病的贡献 AD大脑的环境；以及2)决定性激素在建立 阿尔茨海默病大脑中的炎症反应。在第一个目标下，将结合AD的5xFAD小鼠模型 用四核心基因型(FCG)小鼠来分离AD背景下的染色体和性腺性别。 将使用生物化学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。对于第二个目的，5xFAD小鼠的大脑将被阳性化或 女性化新生儿，以确定性腺激素对炎症过程的影响。创新 这个项目的特点在于：1)在AD模型中没有考虑性别的方面，2)细胞的贡献 在发育过程中以以前没有考虑过的方式区分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学 不同之处。对导致免疫失调和免疫失调的机制提供了关键的见解 阿尔茨海默病的神经炎症很重要，因为它们有可能成为新的 治疗策略。

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.