TREM2-endogenous ligand interactions in Alzheimer disease

项目总结 激活髓系细胞上表达的受体2(TREM2)的单一氨基酸变体已被发现 全基因组关联研究确定为晚发的最强遗传风险因素之一 阿尔茨海默病(AD)。TREM2的AD相关变异体削弱了TREM2的S结合和信号传导能力 对内源性配体的反应。TREM2在阿尔茨海默病中的分子机制尚不完全 理解，部分原因是缺乏确凿的身份为TREM2的S内源配体和缺乏 了解不同内源性配体如何与TREM2相互作用影响TREM2 功能。中心假说是TREM2碱性位点上与AD相关的变体变构 调节结合在TREM2疏水位点的内源配体，以及变构共刺激 碱性和疏水结合部位的内源性配体可增强TREM2的免疫活性 在公元后。目的是确定结合在碱性和/或疏水位点的内源性配体。 TREM2，确定配基结合在任一结合部位的变构效应，并确定 内源性配体上与TREM2结合的AD相关TREM2变体。我们将检验这一假设 并以三个目标来实现目标。目标1是确定碱性和碱性的内源配体 TREM2上的疏水结合部位。目的2确定内源性配体的变构效应 在两个TREM2结合位点上结合。目的3是确定与AD相关的TREM2变体的影响 内源性配体与TREM2结合的研究。 新知识可能会对AD的研究和治疗产生很大影响，因为它开启了一种未被认识到的 以TREM2碱性和疏水位点为靶点识别TREM2内源配体和 促进TREM2调节的免疫激活。研究成果有助于小说的发展 增强TREM2介导的细胞活性的治疗策略，如联合药物治疗 并通过AD相关突变体补偿TREM2功能的丧失，用于AD治疗。虽然 这项研究的直接潜在应用是AD的发病机制，对其他神经退行性变和 受TREM2激活影响的炎症性疾病可能是巨大的。 创新包括1)这将是第一个通过靶向TREM2内源配体来识别TREM2内源配体的研究 TREM2碱性和疏水结合位点使用组合In Silico以更确凿的方式 虚拟筛查、生物物理和生物学实验；2)结果将揭示AD- TREM2碱基结合变构调节结合在TREM2上的内源配体 疏水位点，以及碱基和疏水位点内源配体的变构共刺激 可增强TREM2调节的AD免疫活性，为AD的病因研究提供新的视角。

PROJECT SUMMARY Single amino acid variants in triggering receptor expressed on myeloid cells 2 (TREM2) have been identified by genome-wide association studies to be one of the strongest genetic risk factors for late-onset Alzheimer’s disease (AD). AD-associated variants in TREM2 impair TREM2’s ability to bind and signal in response to endogenous ligands. The molecular mechanisms of TREM2 in AD remain not fully understood, in part due to the lack of conclusive identities for TREM2’s endogenous ligands and the lack of a good understanding of how different endogenous ligands interact with TREM2 to affect TREM2 functions. The central hypothesis is that AD-associated variants at TREM2 basic site allosterically regulate endogenous ligands bound at the hydrophobic site of TREM2, and allosteric co-stimulation by endogenous ligands at both basic and hydrophobic binding sites could enhance TREM2 immune activity in AD. The objective is to identify endogenous ligands that bind at the basic and/or hydrophobic sites of TREM2, determine the allosteric effects of ligand binding at either binding site, and determine the effect of AD-associated TREM2 variants on endogenous ligands binding to TREM2. We will test the hypothesis and implement the objective with three Aims. Aim 1 is to identify endogenous ligands of the basic and hydrophobic binding sites on TREM2. Aim 2 is to determine the allosteric effects of endogenous ligand binding at both TREM2 binding sites. Aim 3 is to determine the effect of AD-associated TREM2 variants on endogenous ligands binding to TREM2. New knowledge could have high impact for AD research and treatment by opening an unrecognized avenue of targeting both TREM2 basic and hydrophobic sites to identify TREM2 endogenous ligands and to promote TREM2-regulated immune activation. Research outcomes could aid the development of novel therapeutic strategies, such as combined drug therapy, to enhance TREM2-mediated cellular activities and to compensate the loss of TREM2 function by AD-associated variants for AD treatment. Although immediate potential application for this study is AD pathogenesis, impact on other neurodegenerative and inflammatory diseases affected by TREM2 activation may be enormous. Innovations include 1) this will be the first study to identify TREM2 endogenous ligands by targeting both TREM2 basic and hydrophobic binding sites in a more conclusive manner using the combined in silico virtual screening, biophysical and biological experiments; 2) Results will unveil novel findings that AD- associated variants at TREM2 basic site allosterically regulate endogenous ligand bound at TREM2 hydrophobic site, and allosteric co-stimulation by endogenous ligands at both basic and hydrophobic sites could enhance TREM2-regulated immune activity in AD, providing novel insight into etiology of AD.