Central and Peripheral Roles of TREM2 in Alzheimer's Disease

 描述(申请人提供)：阿尔茨海默病(AD)是老年人痴呆症最常见的原因，现在是美国第三大主要死亡原因。AD的特点和诊断是以独特的神经病理改变为特征，包括微管相关蛋白tau的神经元内聚集体内的β-淀粉样蛋白(Aβ)多肽的细胞外沉积和明显的神经炎症。然而，神经炎症与AD的各种脑病理和临床转归之间的确切机制关系以及脑内驻留的小胶质细胞和浸润性外周免疫细胞在这些过程中各自所起的作用尚不清楚。最近的遗传学和系统生物学研究表明，多种先天免疫信号通路在晚发性AD发病中起作用。最重要的是，发现了罕见的TREM2杂合编码突变，这是一种仅由髓系细胞表达的基因，显著增加了AD和其他神经退行性疾病的风险。我们的初步发现表明，在Aβ病理的小鼠AD模型和人类AD模型中，TREM2表达上调。此外，共定位研究表明，TREM2在接近Aβ沉积的髓系细胞中选择性上调，但在髓系细胞中不表达 离A较远的细胞β沉积。值得注意的是，仔细的流式细胞术和免疫组织化学分析显示，在AD小鼠模型的大脑中，TREM2在细胞内上调，这些细胞带有反映其潜在来源的标志物，这些标志物来自循环中的炎性单核细胞。与这些发现一致，初步分析显示，人类AD血液样本中的TREM2+细胞增加。此外，在AD小鼠模型中，TREM2缺乏导致Aβ沉积周围的髓系细胞几乎缺失，并导致AD样病理的总体减少。最后，核受体激动剂选择性地靶向这些斑块相关的TREM2+细胞并促进吞噬功能。目前的协作和跨学科研究中需要验证的假设是，脑内驻留的小胶质细胞和血液来源的TREM2+炎性单核细胞在调节AD病理过程中发挥着独特的作用，这可能提供新的生物标志物/诊断，也可以作为靶向治疗。这些研究将利用最先进的AD小鼠模型、结构性TREM2基因敲除小鼠、能够在不同髓系细胞群中缺失TREM2的转基因小鼠、详细的流式细胞术和全基因组基因表达分析以及神经病理学和行为来检查该提案的三个具体目标：1.检查TREM2+细胞在小鼠模型和人类AD模型中的身份、定位和基因表达谱。2.确定TREM2在AD病理调控中的中枢和外周作用。3.治疗性靶向TREM2+细胞。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the third major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the β-amyloid (Aβ) peptide intraneuronal aggregates of the microtubule associated protein tau (MAPT) and marked neuroinflammation. However, the exact mechanistic relationship between neuroinflammation and the various brain pathologies and clinical outcomes in AD remains unclear as well as the respective roles of brain resident microglia and infiltrating peripheral immune cells in these processes. Recent genetic and system biology studies have implicated multiple innate immune signaling pathways in late-onset AD. Most importantly, rare heterozygous coding mutations in TREM2, a gene exclusively expressed by myeloid cells were identified that substantially increase risk for AD and other neurodegenerative diseases. Our preliminary findings demonstrate that TREM2 is upregulated in mouse models of AD with Aβ pathology and human AD. Furthermore, co-localization studies demonstrated that TREM2 is selectively upregulated within myeloid cells in close proximity to Aβ deposits, but not in myeloid cells further away from Aβ deposits. Strikingly, careful flow cytometry and immunohistochemical analyses of brains from mouse models of AD revealed that TREM2 is upregulated within cells that bear markers reflective of their potential origin from circulating inflammatory monocytes. Consistent with these findings, preliminary analysis revealed an increase in TREM2+ cells in human AD blood samples. Furthermore, TREM2 deficiency in an AD mouse model leads to a virtual absence of the myeloid cells surrounding Aβ deposits and an overall reduction in AD-like pathologies. Finally, nuclear receptor agonists selectively target these plaque-associated TREM2+ cells and promote phagocytosis. The hypothesis to be tested in the current collaborative and interdisciplinary studies is that brain resident microglia and blood-derived TREM2+ inflammatory monocytes play distinctive roles in regulating AD pathologies that could provide novel biomarkers/diagnostics and also be targeted therapeutically. These studies will utilize state-of-the art mouse models of AD, constitutive Trem2 knockout mice, transgenic mice enabling deletion of TREM2 in various myeloid cell populations, detailed flow cytometry and genome-wide gene expression analyses as well as neuropathology and behavior to examine the three Specific Aims of the proposal: 1. Examine the Identity, Localization and Gene Expression Profiles of TREM2+ Cells in Mouse Models and Human AD. 2. Determine the Central and Peripheral Role of TREM2 in Regulating AD Pathologies. 3. Therapeutically Targeting TREM2+ Cells.