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展中的作用 摘要 最近的系统生物学研究和GWAS已经证实了小胶质细胞免疫应答在免疫系统中的主导作用。 增加晚发性阿尔茨海默病（LOAD）的风险。同时，在AD模型小鼠中的研究表明， 健康的小胶质细胞功能随着淀粉样蛋白病理学的进展而丧失，并表明疾病修饰 先天免疫反应的组分可以被靶向以减缓或停止疾病进展。近几 在AD模型小鼠的转录组研究中，我们将TREM1鉴定为在小胶质细胞中高度诱导的基因， 与小胶质细胞适应不良反应有关。TREM1及其抗炎相关TREM2， 通过最近在基因调控网络中鉴定的衔接子信号蛋白DAP 12进行信号传导 分析作为参与AD风险增加的免疫基因的最高调节因子。此外，公布的数据 炎症的外周模型证明了TREM1在放大炎症的毒性方面的关键作用。 先天免疫反应和恶化的疾病进展和结果。最近的遗传学研究 TREM1基因座显示TREM1中的内含子变体与CERAD病理学增加相关 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模型中的反应。TREM1是一种炎性膜受体，在骨髓细胞上表达， 谱系细胞TREM1在其作为炎症反应的有效放大器的功能方面是独特的，其中它 仅与经典模式的激活相关， 识别受体在这里，我们将测试这一假设，即在AD的发展过程中，TREM1诱导了一种新的免疫反应。 小胶质细胞对积累的AAP10肽组装体的适应不良免疫应答， 神经元损伤和行为障碍。我们将使用体外药理学和体内 在AD模型小鼠中的条件性敲除策略来测试该假设。我们的研究将决定 TREM1放大了小胶质细胞对积累的ARAP4肽的适应不良反应，以及TREM1是否可以 代表了一种新的免疫靶点，以减缓在临床前和早期临床阶段向AD的进展。

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.