Defining the Mechanisms by Which MS4A Genes Regulate TREM2 in Alzheimer Disease

定义 MS4A 基因在阿尔茨海默病中调节 TREM2 的机制

• 批准号: 10433975
• 负责人: Celeste Marie Karch
• 金额: $ 56.77万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433975
• 关键词: Age; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Antibodies; Biochemical; Biology; Brain; CRISPR/Cas technology; Cell Nucleus; Cell Survival; Cells; Cerebrospinal Fluid; Cognitive; Complex; Culture Media; Data; Development; Disease; Disease model; Event; Exhibits; Extracellular Domain; Functional disorder; Gene Cluster; Genes; Genetic; Genetic Models; Genomics; Genotype; Goals; Human; Human Genetics; Inflammatory Response; Integral Membrane Protein; Knock-out; Maps; Mediating; Membrane Proteins; Meta-Analysis; Metabolism; Microglia; Molecular; Mus; Myeloid Cells; Needles; Nerve Degeneration; Neurodegenerative Disorders; Orthologous Gene; Pathogenesis; Pathway interactions; Patients; Phagocytosis; Pharmacology; Predisposition; Prevention; Proteins; Receptor Signaling; Role; Signal Transduction; TREM2 gene; Testing; Variant; brain cell; cell type; gene function; high risk; human model; induced pluripotent stem cell; knock-down; new therapeutic target; novel; prevent; rare variant; stem cell model; stem cells; targeted treatment; tau Proteins; trafficking; transcriptome sequencing; uptake

Project Description The complex molecular events that underlie the development of Alzheimer's disease (AD) are poorly understood and are the key to developing targeted therapies. Our group and others have shown that rare variants in the triggering receptor expressed on myeloid cells 2 gene (TREM2) are associated with increased susceptibility to AD. TREM2 encodes a membrane protein that is part of a receptor-signaling complex that modulates inflammatory responses, phagocytosis and cell survival in myeloid cells, such as microglia. However, the specific role of TREM2 in AD pathogenesis remains unclear. CSF sTREM2 levels are increased in patients with symptomatic AD compared to cognitively normal controls. We have recently discovered that common variants in the MS4A locus are a major regulator of CSF sTREM2 levels. Importantly, the same allele associated with higher CSF sTREM2 levels is associated lower AD risk and delayed age at onset. We also identified a second, independent signal in the MS4A locus that encodes MS4A4A p.M159V, which has the opposite effect on CSF sTREM2 levels and AD risk. Our findings that two independent signals in the MS4A gene region have opposing effects on CSF sTREM2 levels and AD risk points to the connection between MS4A and TREM2 biology in AD pathogenesis. The goal of this project is to elucidate the mechanisms by which MS4A genes alter TREM2 function and drive AD pathogenesis. We hypothesize that MS4A4A is involved in TREM2 trafficking and cleavage and that disrupted interaction between MS4A4A and TREM2 leads to microglial dysfunction and neurodegeneration. To test this hypothesis, we will use genomic and biochemical approaches in human brains and stem cell models. The results of this project will provide the mechanistic framework needed to develop treatments that restore or enhance TREM2 functions in order to prevent neurodegenerative disease.

项目描述 阿尔茨海默病（AD）发展背后的复杂分子事件目前尚不清楚 理解并是开发靶向治疗的关键。我们的团队和其他人已经表明，罕见的 骨髓细胞 2 基因 (TREM2) 上表达的触发受体的变异与增加 对 AD 的易感性。 TREM2 编码一种膜蛋白，该蛋白是受体信号复合物的一部分， 调节骨髓细胞（如小胶质细胞）的炎症反应、吞噬作用和细胞存活。 然而，TREM2在AD发病机制中的具体作用仍不清楚。 CSF sTREM2 水平升高 与认知正常对照相比，有症状的 AD 患者。我们最近发现 MS4A 基因座的常见变异是脑脊液 sTREM2 水平的主要调节因子。重要的是，相同的等位基因 较高的脑脊液 sTREM2 水平与较低的 AD 风险和延迟的发病年龄相关。我们也 在编码 MS4A4A p.M159V 的 MS4A 基因座中鉴定出第二个独立信号，该信号具有 对 CSF sTREM2 水平和 AD 风险产生相反的影响。我们的研究结果表明 MS4A 中有两个独立的信号 基因区域对 CSF sTREM2 水平有相反的影响，AD 风险点与之间的联系 AD 发病机制中的 MS4A 和 TREM2 生物学。该项目的目标是通过以下方式阐明其机制： MS4A 基因改变 TREM2 功能并驱动 AD 发病机制。我们假设 MS4A4A 是 参与 TREM2 运输和切割，并扰乱 MS4A4A 和 TREM2 引线之间的相互作用 小胶质细胞功能障碍和神经退行性变。为了检验这个假设，我们将使用基因组学和生物化学 人脑和干细胞模型中的方法。该项目的结果将提供机械 开发恢复或增强 TREM2 功能的治疗方法所需的框架，以预防 神经退行性疾病。