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

PLCG2 阿尔茨海默病风险变异对小胶质细胞生物学和疾病发病机制的影响

• 批准号: 10317333
• 负责人: STEPHANIE J BISSEL
• 金额: $ 233.37万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317333
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Attenuated; Behavioral; Biological Assay; Biology; Brain; Cells; Central Nervous System Diseases; Cessation of life; Chronic Lymphocytic Leukemia; Cognition; Complex; Data; Development; Disease; Disease Progression; Drug resistance; Elements; Enzymes; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genetic study; Human; Immune response; Immune signaling; Immunologic Receptors; Impaired cognition; Impairment; Individual; Innate Immune Response; Investigation; Knock-out; Laboratories; Link; Measures; Mediating; Membrane; Memory; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Neurodegenerative Disorders; Neurons; PLCG2 gene; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Patients; Performance; Phagocytes; Phenotype; Risk; Rodent Model; Role; Severity of illness; Signal Pathway; Signal Transduction; TREM2 gene; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Transcriptional Regulation; Variant; brain tissue; cell type; cytokine; effective therapy; experimental study; gain of function; genetic variant; genome wide association study; genomic locus; immune function; improved; induced pluripotent stem cell; loss of function; macrophage; mild cognitive impairment; mouse model; novel; risk variant; tau Proteins; tau-1; therapeutic target; transcription factor; β-amyloid burden

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.

项目摘要 阿尔茨海默氏病（AD）和其他神经退行性疾病的特征是强大 小胶质细胞介导的免疫反应。遗传研究表明，许多 会议改变AD风险的基因是参与先天免疫反应的基因，并且是 主要在小胶质细胞中表达，包括磷脂酶C伽马2（PLCG2）。 PLCG2是一个 各种免疫接收器的关键信号传导元件，是关键的调节枢纽基因 免疫信号传导。该提案的主要目的是确定PLCG2在AD中的作用 发病。 GWAS研究表明，PLCG2 P522R变体与 AD风险降低。我们的实验室已经确定了一种新颖的SNP（RS617749044） 编码PLCG2 M28L变体的AD升高风险。此应用程序中的总体目标是 阐明使用AD的啮齿动物模型这些PLCG2变体对AD发病机理的影响 并剖析PLCG2变体改变小胶质细胞功能的分子机制。这 假设是M28L变体是功能等位基因的丧失，相反，P522R为 在我们的鼠模型中，关于AD发病机理的保护性。提出的实验 该应用程序完全新颖，首次允许进行独特的，全面的分析 广告风险基因的遗传变异会议会议既有保护和广告的风险。初步数据 申请人生成的表明，在AD啮齿动物模型中，M28L变体具有 加速和恶化的疾病相关病理，相反，p522r变体 似乎减轻了疾病的严重程度和进展。假设将通过 追求三个具体目的：1）确定随着损失和增益改变的广告相关表型 AD淀粉样蛋白生成模型中的功能PLCG2变体； 2）确定分子特征和 小胶质细胞的途径与保护性或风险PLCG2变体相关的途径 AD的淀粉样生成模型； 3）评估PLCG2变体的机制 影响小胶质细胞内的细胞内信号传导。这些研究是必需的先决条件 PLCG2定向治疗的开发。