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（Alzheimer's disease，AD）是老年人最常见的神经退行性疾病。补体 级联反应是先天免疫系统的一种强大的效应机制，可以被原纤维直接激活。 Aβ在这种炎症情况中是一个参与者。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的进展。补体激活片段C5 a一直是一种 主要的焦点，因为其促炎受体C5 aR 1的抑制导致小胶质细胞的活化减少， 星形胶质细胞，神经元复杂性的保存和AD模型中认知丧失的减少。这些关键 观察结果强烈提示C5 a与其受体C5 aR 1的结合启动细胞活化，从而导致变化 在小胶质细胞和星形胶质细胞中的蛋白质表达中，其导致病理表型和疾病 进展该提案的主要目标是系统地了解细胞特异性蛋白质的改变， 在阿尔茨海默病的背景下，由C5 a-C5 aR 1信号传导引起的表达。具体而言，这将 将我们对特定RNA诱导的知识扩展到蛋白质的产生，以及每种RNA的贡献， 这些功能性蛋白质最终加速了发病机制和神经元功能障碍， 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.