Toll-Like Receptor Signaling in Alzheimer's Disease

小胶质细胞是大脑的主要先天免疫细胞。在阿尔茨海默病(AD)中，这些细胞与B-淀粉样蛋白(AB)结合，并聚集在AB沉积的部位，包括老年斑。小胶质细胞与AB的相互作用促进慢性炎症反应，其特征是产生促炎细胞因子和趋化因子、活性氧和氮物种以及补体蛋白。这种无菌炎症是由AB持续激活小胶质细胞维持的，并导致神经元退化和AB沉积增加，从而促进疾病进展。结合AB的受体以及AB触发的促进慢性炎症的信号通路尚不完全清楚。我们的长期目标是确定AB激活小胶质细胞的分子机制以及这些途径在AD发病机制中的影响。我们推测，Toll样受体(TLR)是一种进化上古老的模式识别受体家族，用于检测微生物配体，启动并维持对AB的小胶质细胞炎症反应。这一假说是基于初步的发现，即靶向缺失TLR信号适配器MyD88可以在体外和体内消除小胶质细胞对AB的炎症反应。在这项提案中，我们将定义负责启动这一信号的TLRs和辅助受体，它们对小胶质细胞炎症反应的影响以及对疾病的影响。具体地说，我们将(1)在体外确定TLR连接和信号在小胶质细胞对AB反应中的作用，(2)确定AB辅助受体在促进TLR信号转导中的作用，以及(3)在体内确定AB-TLR信号在阿尔茨海默病病理中的影响。了解小胶质细胞与AB相互作用的机制(S)并确定参与这些相互作用的受体将有助于深入了解这些细胞在AD发病机制中的作用，并可能确定AD的治疗靶点，以促进AB的小胶质细胞清除，同时下调其神经毒性作用。

Microglia are the principal innate immune cells of the brain. In Alzheimer's disease (AD) these cells bind B-amyloid (AB) and accumulate at sites of AB deposition, including senile plaques. Microglial interactions with AB promote a chronic inflammatory response characterized by the production of pro-inflammatory cytokines and chemokines, reactive oxygen and nitrogen species, and complement proteins. This sterile inflammation is maintained by persistent microglial activation by AB and leads to neuronal degeneration and increased AB deposition and therefore promotes disease progression. The receptors that bind AB and the signaling pathways triggered by AB that promote chronic inflammation are not fully understood. Our long-term goals are to identify the molecular mechanisms of microglial activation by AB and the impact of these pathways on AD pathogenesis. We hypothesize that Toll-like receptors (TLR), an evolutionarily ancient family of pattern recognition receptors that detect microbial ligands, initiate and maintain the microglial inflammatory response to AB . This hypothesis is based on preliminary findings that targeted deletion of the TLR signaling adaptor MyD88 abrogates microglial inflammatory responses to AB in vitro and in vivo. In this proposal, we will define the TLRs and co-receptors responsible for initiating this signaling, their impact on microglial inflammatory responses and the implications for disease. Specifically, we will (1) Define the role of TLR ligation and signaling on microglial responses to AB in vitro, (2) Determine the role of AB co-receptors in facilitating TLR signaling, and (3) Determine the impact of AB -TLR signaling on Alzheimer's disease pathology in vivo. Understanding the mechanism(s) of microglial interactions with AB and identifying the receptors involved in these interactions will provide valuable insight into the role of these cells in the pathogenesis of AD and potentially identify therapeutic targets in AD to promote microglial clearance of AB while downregulating their neurotoxic effects.