TREM2 dependent microglial function and dysfunction: A target for therapeutic modulation of Alzheimer's disease and Frontotemporal Dementia

TREM2 依赖性小胶质细胞功能和功能障碍：阿尔茨海默病和额颞叶痴呆的治疗调节靶点

• 批准号: 394585134
• 负责人: Professor Dr. Christian Haass
• 金额: --
• 依托单位: Munich Cluster for Systems Neurology (SyNergy)
• 依托单位国家: 德国
• 项目类别: Reinhart Koselleck Projects
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/394585134?language=en
• 关键词: TREM2; dependent; microglial; function; dysfunction

I want to investigate function and dysfunction of the triggering receptor expressed on myeloid cells 2 (TREM2), which plays a central role in regulating microglial activity and is genetically associated with late onset Alzheimer's disease (AD) and other neurodegenerative disorders. The primary goal of this application is to determine the possibility if TREM2 dependent microglial responses to amyloid plaque pathology may be beneficial and could be exploited to modulate disease progression. Since TREM2 function is associated with phagocytosis, I will investigate if a TREM2 dependent microglial function affects seeding and spreading of amyloid pathology via clearance mechanisms. Moreover, since evidence exists that TREM2, Progranulin (GRN) and Apolipoprotein E (ApoE), which all modulate AD, are strongly upregulated in microglia during disease progression, I will generate mouse reporter lines allowing to determine the spatiotemporal distribution of TREM2, GRN, and ApoE expressing microglia in relation to amyloid plaques or other neuronal lesions with the additional goal to search for functionally distinct microglial subpopulations. Since we recently found that microglia cluster via a TREM2 dependent chemotaxis around amyloid plaques, I hypothesize that microglia may form a microenvironment in which ApoE is selectively enriched. This would drive Amyloid -peptide (A) aggregation but at the same time also allow increased phagocytic clearance of amyloid plaques. As cell autonomous TREM2 signaling depends on its surface transport and is terminated by ADAM 10/17 mediated shedding, modulation of TREM2 cleavage may be a therapeutic strategy to stimulate TREM2 dependent signaling. We recently identified a unique cleavage site of TREM2 C-terminal to histidine 157. Based on this finding I want to generate antibodies, which prevent access of ADAM10/17 to the cleavage site and therefore selectively preserve full-length TREM2 and its cell autonomous signaling activity.

我想研究髓样细胞上表达的触发受体2(TREM2)的功能和功能障碍，它在调节小胶质细胞活动方面发挥核心作用，并与晚发性阿尔茨海默病(AD)和其他神经退行性疾病有遗传关联。这项应用的主要目标是确定依赖TREM2的小胶质细胞对淀粉样斑块病理的反应是否可能是有益的，并可用于调节疾病的进展。由于TREM2功能与吞噬功能有关，我将研究TREM2依赖的小胶质细胞功能是否通过清除机制影响淀粉样蛋白病理的播种和传播。此外，由于有证据表明，在疾病进展过程中，调节AD的TREM2、前颗粒蛋白(GRN)和载脂蛋白E(ApoE)在小胶质细胞中强烈上调，我将建立小鼠报告系，以确定表达TREM2、GRN和ApoE的小胶质细胞与淀粉样斑块或其他神经元损伤相关的时空分布，并寻找功能不同的小胶质细胞亚群。由于我们最近发现小胶质细胞通过依赖于TREM2的趋化作用聚集在淀粉样斑块周围，我推测小胶质细胞可能形成了一个选择性地富含载脂蛋白E的微环境。这将推动淀粉样蛋白-肽(A)聚集，但同时也允许淀粉样蛋白斑块的吞噬清除增加。由于细胞自主的TREM2信号依赖于其表面转运，并被ADAM 10/17介导的脱落终止，因此调节TREM2的裂解可能是刺激TREM2依赖信号的一种治疗策略。我们最近发现了TREM2 C-末端与组氨酸157的一个独特的裂解位点。基于这一发现，我想产生抗体，阻止ADAM10/17进入切割位点，从而选择性地保留全长TREM2及其细胞自主信号活性。