Assessing cell specific proteomes in the presence and absence of C5a complement signaling in Alzheimer's disease models

项目摘要。 阿尔茨海默病(AD)是老年人最常见的神经退行性疾病。补语 级联，先天免疫系统的一种强大的效应机制，可以被纤维直接激活 一名β，被牵连到这一煽动性场景中。在大脑中，大多数补体成分的表达 在衰老过程中增加，并在AD患者和AD动物模型中进一步增加，这与 补体免疫激活在疾病进展中的作用。补体激活片段C5a是一种 主要焦点是抑制其前炎性受体C5aR1，导致小胶质细胞激活减少和 星形胶质细胞，保存神经元的复杂性和减少阿尔茨海默病模型的认知损失。这些关键因素 观察有力地表明，C5a与其受体C5aR1结合后启动细胞激活，导致改变 在小胶质细胞和星形胶质细胞中的蛋白表达，导致病理表型和疾病 进步。这项提议的主要目标是系统地了解细胞特异性蛋白质的变化。 在阿尔茨海默病的背景下，通过C5a-C5aR1信号转导产生的表达。具体来说，这将是 扩展我们对特定RNA诱导产生蛋白质的知识，以及每个RNA对蛋白质生产的贡献 细胞类型到这些功能蛋白，最终加速发病和神经元功能障碍。 阿尔茨海默病模型。

Project Summary. Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of the elderly. The complement cascade, a powerful effector mechanism of the innate immune system that can be directly activated by fibrillar Aβ, is implicated as a player in this inflammatory scenario. In brain, expression of most complement components increases during aging and further increases in AD patients and animal models of AD, consistent with a role for complement immune activation in progression of the disease. Complement activation fragment C5a has been a major focus, as inhibition of its proinflammatory receptor, C5aR1, leads to less activation of microglia and astrocytes, preservation of neuronal complexity and reduction of cognitive loss in AD models. These critical observations strongly suggest C5a binding to its receptor C5aR1 initiates cellular activation leading to changes in protein expression in microglia and astrocytes, which result in pathological phenotypes and disease progression. The primary goal of this proposal is to systemically understand alterations in cell-specific protein expression that result from signaling via C5a-C5aR1 in the context of Alzheimer’s disease. Specifically, this will extend our knowledge of induction of specific RNAs to production of the proteins, and the contribution of each cell type to those functional proteins, that ultimately accelerate pathogenesis and neuronal dysfunction in Alzheimer’s disease models.