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

项目说明 阿尔茨海默病(AD)发生的复杂分子事件并不多见 了解并是开发靶向治疗的关键。我们的团队和其他人已经证明了这种罕见的 髓系细胞2基因(TREM2)上表达的触发受体的变异与 阿尔茨海默病的易感性。TREM2编码一种膜蛋白，它是受体信号复合体的一部分， 调节炎症反应，吞噬和细胞存活的髓系细胞，如小胶质细胞。 然而，TREM2在AD发病机制中的具体作用尚不清楚。脑脊液sTREM2水平升高 在有症状的AD患者中与认知正常的对照组进行比较。我们最近发现， MS4A基因座的常见变异是脑脊液sTREM2水平的主要调节因素。重要的是，相同的等位基因 与较高的脑脊液sTREM2水平相关的是较低的AD风险和发病延迟年龄。我们也 在编码MS4A4A p.M159V的MS4A基因座中发现了第二个独立的信号，它具有 对脑脊液sTREM2水平和AD风险的相反影响。我们的发现在MS4A中有两个独立的信号 基因区域对脑脊液sTREM2水平和AD危险点之间的联系具有相反的影响 MS4A和TREM2在AD发病机制中的生物学作用这个项目的目标是通过以下方式阐明这些机制 哪些MS4A基因改变TREM2功能并驱动AD的发病。我们假设MS4A4A是 参与了TREM2的贩运和切割，并扰乱了MS4A4A和TREM2导线之间的相互作用 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中的方法。这一项目的成果将提供机械的 需要一个框架来开发恢复或增强TREM2功能的治疗方法，以防止 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.