Microglia ontogeny, proliferation and maturation in Alzheimer's Disease

项目摘要： 神经炎症在中枢神经系统(CNS)的损伤和变性中起着关键作用。 小胶质细胞(MG)是中枢神经系统中特有的髓样细胞，在先天免疫中发挥重要作用 回应。MG还在中枢神经系统发育、可塑性和免疫监视中发挥重要作用。中枢神经系统损伤 神经退行性变导致MG的炎症激活。被激活的MG执行动态功能 对神经元健康既有支持作用，也有破坏性作用。成人中枢神经系统MG的周转非常缓慢 但在人口减少或受伤后，新的MG可能会迅速产生。然而，个体发生学 成人中枢神经系统中的新MG尚不完全清楚。而MG祖细胞(MGP)则在 发育中的大脑是在胚胎的卵黄囊中出生的，最近的报道表明MGP细胞也可能存在于 成年中枢神经系统。因此，MG的可塑性可能不仅仅是指存在的分子和形态的变化 细胞，而且还产生了新的MG种群。目前，人们对其潜在作用知之甚少。 阿尔茨海默病(AD)中新生的小胶质细胞。我们有兴趣了解MG的监管 行为，包括新生MG在神经退行性变背景下的生成和分化。 我们已经开发出新的方法来绘制和分离一组表达两种标记的细胞 成年小鼠大脑的祖细胞状态(显著蛋白1)和髓系承诺(CD45)。这一潜力 未损伤的成体中枢神经系统中存在祖细胞群体，可通过荧光激活细胞进行分离 在体外和体内诱导分化为成熟的MG。这项提案的目标是1) 确定AD病理是否影响新生MG的增殖、分化和存活 成人中枢神经系统，2)确定MGP是否与淀粉样蛋白相关的小胶质细胞群有关 斑块，3)检查AD病理是否影响成人的表观遗传学特征和转录组 MGP和4)确定MGP来源的成熟小胶质细胞的炎症激活模式是否 受细胞年龄或起源的影响。我们将使用发展为早期淀粉样斑块的AD小鼠模型 为了确定这些阿尔茨海默病的病理特征是否会影响祖细胞和 成熟的MG种群。此外，我们计划采用最先进的单细胞测序方法来 研究阿尔茨海默病的病理如何影响染色质结构和基因表达 中枢神经系统髓系细胞群。总之，实现这些目标将有助于进一步 了解MG的种群动态及其对炎症性疾病的影响 阿尔茨海默病脑内反应。

PROJECT ABSTRACT: Neuroinflammation plays a critical role in injury and degeneration in the central nervous system (CNS). Microglia (MG) are specialized resident myeloid cells in the CNS that play essential roles the innate immune response. MG also have essential roles in CNS development, plasticity and immune surveillance. CNS injury and neurodegeneration lead to inflammatory activation of MG. Activated MG perform dynamic functions that can be both supportive and destructive to neuronal health. In the adult CNS MG turnover occurs very slowly but new MG can be rapidly generated after depopulation or in response to injury. However the ontogeny of new MG in the adult CNS is still not fully understood. While MG progenitors (MGP) that colonize the developing brain are born in the embryonic yolk sac, recent reports suggest that MGP cells may also exist in the adult CNS. Thus MG plasticity may not only refer to the molecular and morphological changes of existing cells, but also the generation of new MG populations. Currently, little is known regarding the potential role of newly born microglia in Alzheimer's disease (AD). We are interested in understanding the regulation of MG behavior, including the generation and differentiation of newly born MG in the setting of neurodegeneration. We have developed novel methods to fate map and isolate a population of cells expressing both markers of progenitor state (prominin 1) and myeloid commitment (Cd45) from the adult mouse brain. This potential progenitor population is present in the uninjured adult CNS, can be isolated by fluorescence activated cell sorting (FACS) and will differentiate into mature MG in vitro and in vivo. The goals of this proposal are to 1) determine if AD pathology influences the proliferation, differentiation, and survival of newly born MG in the adult CNS, 2) to determine if MGP contribute to the microglia population associated with amyloid plaque, 3) examine whether AD pathology influences the epigenetic profile and transcriptome of adult MGP and 4) determine if the inflammatory activation pattern in MGP derived mature microglia is influenced by cellular age or origin. We will employ mouse models of AD that develop early amyloid plaque to determine if these pathological hallmarks of AD influence the population dynamics of the progenitor and mature MG populations. In addition, we plan to employ state of the art single cell sequencing approaches to study how AD pathology influences chromatin architecture and gene expression in these distinguishable populations of CNS myeloid cells. In summary, the accomplishment of these aims will help to further understand dynamics of MG populations and the influence of those population dynamics on the inflammatory response in AD brain.