Central and Peripheral Roles of TREM2 in Alzheimer's Disease

 描述（由申请人提供）：阿尔茨海默病（AD）是老年痴呆症的最常见原因，目前是美国第三大死亡原因。AD的特征和诊断是独特的神经病理学改变，包括β-淀粉样蛋白（Aβ）肽的细胞外沉积、微管相关蛋白tau（MAPT）的神经元内聚集和显著的神经炎症。然而，神经炎症与AD中的各种脑病理和临床结果之间的确切机制关系以及脑驻留小胶质细胞和浸润性外周免疫细胞在这些过程中的各自作用仍不清楚。最近的遗传学和系统生物学研究表明，迟发性AD中存在多种先天免疫信号通路。最重要的是，TREM 2（一种仅由骨髓细胞表达的基因）中罕见的杂合编码突变被鉴定为显著增加AD和其他神经退行性疾病的风险。我们的初步研究结果表明，TREM 2在具有Aβ病理学的AD小鼠模型和人AD中上调。此外，共定位研究表明，TREM 2在髓样细胞中选择性上调，靠近Aβ沉积物，但在髓样细胞中不上调。 细胞远离Aβ沉积物。引人注目的是，对来自AD小鼠模型的脑的仔细流式细胞术和免疫组织化学分析显示，TREM 2在携带反映其来自循环炎性单核细胞的潜在来源的标志物的细胞内上调。与这些发现一致，初步分析显示人AD血液样品中TREM 2+细胞增加。此外，AD小鼠模型中的TREM 2缺陷导致Aβ沉积物周围的骨髓细胞几乎不存在，并且AD样病理学总体减少。最后，核受体激动剂选择性地靶向这些斑块相关的TREM 2+细胞并促进吞噬作用。在目前的合作和跨学科研究中要测试的假设是，脑内驻留的小胶质细胞和血液来源的TREM 2+炎性单核细胞在调节AD病理学中发挥独特的作用，可以提供新的生物标志物/诊断，也可以在治疗上靶向。这些研究将利用最先进的AD小鼠模型、组成型Trem 2敲除小鼠、能够在各种骨髓细胞群体中缺失TREM 2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的：检查小鼠模型和人AD中TREM 2+细胞的同一性、定位和基因表达谱。 2.确定TREM 2在调节AD病理中的中枢和外周作用。 3.治疗靶向TREM 2+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.