Impact of PLCG2 Alzheimer's Disease Risk Variants on Microglia Biology and Disease Pathogenesis

项目总结 阿尔茨海默病(AD)和其他神经退行性疾病的典型特征是 小胶质细胞介导的免疫反应。遗传学研究已经证明，许多 导致AD风险改变的基因是那些参与先天免疫反应的基因， 主要表达于小胶质细胞，包括磷脂酶C-γ2(PLCG2)。PLCG2是一种 是多种免疫受体的关键信号元件，是一种关键的调节中枢基因 免疫信号。这项建议的主要目标是确定PLCG2在AD中的作用 发病机制。Gwas研究表明，PLCG2 P522R变异体与 同时降低AD风险。我们实验室发现了一个新的SNP(Rs617749044)，该SNP与 编码PLCG2 M28L变体的AD风险增加。这个应用程序的总体目标是 利用AD啮齿动物模型阐明PLCG2突变体在AD发病机制中的作用 并剖析了PLCG2变异体改变小胶质细胞功能的分子机制。这个 假设M28L变异是功能等位基因的丧失，而P522R是功能等位基因的丧失 在我们的小鼠模型中对AD的发病机制具有保护作用。中提出的实验 这一应用程序是全新的，并且第一次允许进行独特的、全面的分析 阿尔茨海默病风险基因的遗传变异对阿尔茨海默病既有保护又有风险。初步数据 由申请人产生的结果表明，在AD的啮齿动物模型中，M28L变体具有 加速和加重与疾病相关的病理，反之，P522R变体 似乎可以减缓疾病的严重程度和进展。这些假设将通过以下方式进行检验 追求三个具体目标：1)确定AD相关表型因得失而改变的表型 阿尔茨海默病淀粉样变性模型中PLCG2的功能变异；2)鉴定分子特征和 小胶质细胞中与PLCG2保护性或危险变异体相关的通路 AD的淀粉样变性模型；3)评估PLCG2变异体的机制 影响小胶质细胞内的信号转导。这些研究是 PLCG2导向疗法的研究进展。

PROJECT SUMMARY Alzheimer’s disease (AD) and other neurodegenerative diseases are typified by a robust microglial-mediated immune response. Genetic studies have demonstrated that many of the genes that confer altered risk for AD are those involved in the innate immune response and are expressed primarily in microglia, including phospholipase C gamma 2 (PLCG2). PLCG2 is a critical signaling element for a variety of immune receptors and is a key regulatory hub gene for immune signaling. The primary objective of this proposal is to determine the role of PLCG2 in AD pathogenesis. GWAS studies have demonstrated that the PLCG2 P522R variant is associated with reduced AD risk. Our laboratory has identified a novel SNP (rs617749044) associated with elevated AD risk encoding the PLCG2 M28L variant. The overall objectives in this application are to elucidate the effect of these PLCG2 variants on AD pathogenesis using rodent models of AD and dissect the molecular mechanisms by which PLCG2 variants alter microglia function. The hypotheses are that the M28L variant is a loss of function allele, and conversely the P522R is protective with respect to AD pathogenesis in our murine models. The experiments proposed in this application are entirely novel and allow, for the first time, a unique, comprehensive analysis of an AD risk gene whose genetic variants confer both protection and risk for AD. Preliminary data generated by the applicant suggests that in a rodent model of AD, the M28L variant had accelerated and exacerbated disease related pathology and conversely the P522R variant appeared to attenuate disease severity and progression. The hypotheses will be tested by pursuing three specific aims: 1) Determine AD-related phenotypes altered by loss and gain of function PLCG2 variants in an amyloidogenic model of AD; 2) Identify molecular signatures and pathways in microglia that are associated with protective or risk PLCG2 variants in an amyloidogenic model of AD; and 3) Evaluate the mechanisms through which PLCG2 variants affect intracellular signaling in microglia. These studies are essential prerequisites for the development of PLCG2-directed therapeutics.