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

项目总结/摘要 尽管已知女性会受到阿尔茨海默病（AD）的影响， 这种差异的潜在生物学尚未解决。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痴呆症，其中炎症起作用， 关键作用。本申请中的总体目标是（i）定义指定 AD脑中的炎症反应，和（ii）阐明这些是否在存在下改变 循环荷尔蒙我们的中心假设是，大脑免疫细胞的性别差异是由 性染色体和性腺类固醇激素，导致不同的炎症过程， AD发作和进展。这个项目的基本原理是，确定遗传和激素 介质有助于在AD的神经炎症过程中的性别差异， 科学框架，从而可以开发新的治疗策略。核心假设是 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;和2）确定性激素在建立AD大脑中的组织效应。 AD脑中的炎症反应。在第一个目标下，将AD的5xFAD小鼠模型与 用四核心基因型（FCG）小鼠在AD的背景下分离染色体和性腺性别。 炎症将使用生物化学和分子技术进行评估，以检查免疫细胞活化 神经元的健康和存活。对于第二个目的，将5xFAD小鼠的大脑雄性化或 雌性化以确定性腺激素对炎症过程的影响。创新 该项目的主要目的在于：1）以前在AD模型中未考虑的性别方面，2）细胞的贡献 在发展过程中的差异，以以前没有考虑的方式AD风险，和3）使用 将疾病模式从蛋白质功能差异转向表达差异的方法 差异为引起免疫失调的机制提供重要见解， 神经炎症在AD中是重要的，因为它们有可能成为新的基础。 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.