The role of TREM1 signaling in the development of Alzheimer’s disease

标题和摘要 TREM1信号在阿尔茨海默病发病中的作用 摘要 最近的系统生物学研究和GWA已经证实，小胶质细胞免疫反应在 增加晚发性阿尔茨海默病(LOAD)的风险。同时，对AD模型小鼠的研究表明 这种健康的小胶质细胞功能随着淀粉样变的进展而丧失，这表明疾病的修改 先天免疫反应的组成部分可以被作为延缓或阻止疾病进展的目标。在最近 在AD模型小鼠的转录组研究中，我们发现TREM1是一个在小胶质细胞中高度诱导的基因，并且 与小胶质细胞适应不良反应相关。TREM1及其抗炎相关的TREM2，均 通过DAP12发出信号，DAP12是最近在基因调控网络中发现的一种适配器信号蛋白 分析作为免疫基因的最高调节器，参与了AD风险的增加。此外，发布的数据在 外周炎症模型显示TREM1在放大TREM1的毒性方面发挥着关键作用 先天免疫反应和恶化的疾病进展和结果。最新的遗传研究 TREM1基因座显示TREM1内含子变异与CERAD病理增加相关 和认知能力下降。在这项提案中，我们将测试TREM1在恶化小胶质细胞免疫中的作用 AD模型的反应。TREM1是一种炎性膜受体，表达于髓系细胞 血统细胞。TREM1的独特之处在于其作为炎症反应的强大放大因子的功能 只有在激活经典模式时才会产生严重的促炎反应 识别受体。在这里，我们将检验这样的假设，即在AD的发展过程中，TREM1诱导 适应不良的小胶质细胞免疫反应积聚的Aü多肽组件加速突触和 神经元损伤和行为障碍。我们将使用体外药理和体内实验相结合的方法 在AD模型小鼠中的条件性基因敲除策略来验证这一假说。我们的研究将决定 TREM1可放大小胶质细胞对积聚多肽的不良适应反应，以及TREM1是否可能 代表了一种新的免疫靶点，可以在临床前和临床早期延缓进展为阿尔茨海默病。

Title and Abstract The role of TREM1 signaling in the development of Alzheimer's disease Abstract Recent systems biology studies and GWAS have confirmed a dominant role of microglial immune responses in increasing risk of late onset Alzheimer's disease (LOAD). In parallel, studies in AD model mice demonstrate that healthy microglial function is lost with advancing amyloid pathology, and suggest that disease-modifying components of the innate immune response could be targeted to slow or halt disease progression. In recent transcriptome studies of AD model mice, we identified TREM1 as a gene highly induced in microglia and highly correlated with microglial maladaptive responses. TREM1, and its anti-inflammatory relative TREM2, both signal through DAP12, an adapter signaling protein that was recently identified in gene regulatory network analyses as a top regulator of immune genes involved in increased risk of AD. Moreover, published data in peripheral models of inflammation demonstrate a pivotal role of TREM1 in amplifying toxic aspects of the innate immune response and worsening disease progression and outcome. Recent genetic studies of the TREM1 locus demonstrate an intronic variant in TREM1 that is associated with increased CERAD pathology and cognitive decline. In this proposal, we will test the role of TREM1 in worsening microglial immune responses in models of AD. TREM1 is an inflammatory membrane receptor that is expressed on myeloid lineage cells. TREM1 is unique in its function as a potent amplifier of inflammatory responses where it generates a severe pro-inflammatory response only in association with activation of classical pattern recognition receptors. Here, we will test the hypothesis that in the development of AD, TREM1 induces a maladaptive microglial immune response to accumulating Aß peptide assemblies that accelerates synaptic and neuronal injury and behavioral impairment. We will use a combination of in vitro pharmacologic and in vivo conditional knockout strategies in AD model mice to test this hypothesis. Our studies will determine whether TREM1 amplifies the maladaptive microglial response to accumulating Aß peptides, and whether TREM1 may represent a novel immune target to slow progression to AD at pre-clinical and early clinical stages.