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

项目摘要 阿尔茨海默氏病（AD）和其他神经退行性疾病的典型特征是由一种强有力的神经退行性疾病引起的。 小胶质细胞介导的免疫反应。遗传学研究表明， 赋予AD风险改变的基因是那些参与先天免疫应答的基因， 主要在小胶质细胞中表达，包括磷脂酶C γ 2（PLCG 2）。PLCG 2是一种 是多种免疫受体的关键信号元件，也是免疫调节的关键调控中心基因。 免疫信号该建议的主要目的是确定PLCG 2在AD中的作用 发病机制GWAS研究表明，PLCG 2 P522 R变异与 降低AD风险。我们的实验室已经确定了一个新的SNP（rs617749044）， 编码PLCG 2 M28 L变体的AD风险升高。本申请的总体目标是 使用AD啮齿动物模型阐明这些PLCG 2变体对AD发病机制的作用 并剖析PLCG 2变异体改变小胶质细胞功能的分子机制。的 假设M28 L变体是功能缺失等位基因，相反，P522 R是 在我们的鼠模型中，对AD发病机制具有保护作用。实验中提出的 这种应用是完全新颖的，并允许，第一次，一个独特的，全面的分析， AD风险基因的遗传变异既能提供AD的保护，又能带来AD的风险。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，M28 L变体具有 加速和加重疾病相关的病理学，反之，P522 R变异 似乎减轻了疾病的严重程度和进展。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相关的表型改变的损失和获得的 在AD的淀粉样蛋白生成模型中的功能PLCG 2变体; 2）鉴定分子特征， 在小胶质细胞中与保护性或风险PLCG 2变体相关的通路， AD的淀粉样蛋白生成模型;以及3）评估PLCG 2变体通过其表达的机制。 影响小胶质细胞的细胞内信号传导。这些研究是实现这些目标的必要先决条件。 PLCG 2导向治疗的发展。

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.