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

项目描述 阿尔茨海默病（AD）发展背后的复杂分子事件很少 这是开发靶向治疗的关键。我们的团队和其他人已经证明， 髓样细胞表达的触发受体2基因（TREM2）的变体与增加的 对AD的易感性TREM2编码一种膜蛋白，它是受体信号复合物的一部分， 调节骨髓细胞如小胶质细胞中的炎症反应、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 在有症状的AD患者中与认知正常的对照组相比。我们最近发现， MS4A基因座中的常见变体是CSF sTREM2水平的主要调节物。重要的是，相同的等位基因 与较高的CSF sTREM2水平相关的是较低的AD风险和延迟的发病年龄。我们也 鉴定了编码MS4A4A p.M159V的MS4A基因座中的第二个独立信号，其具有 对CSF sTREM2水平和AD风险有相反的影响。我们的研究发现，MS4A中的两个独立信号 基因区域对CSF sTREM2水平和AD风险点之间的联系有相反的影响， AD发病机制中的MS4A和TREM2生物学。本项目的目标是阐明机制， 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，并破坏MS4A4A和TREM2前导之间的相互作用 小胶质细胞功能障碍和神经退化为了验证这一假设，我们将使用基因组和生化 人类大脑和干细胞模型的方法。该项目的结果将提供 开发恢复或增强TREM2功能的治疗方法所需的框架， 神经退行性疾病

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.