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，这些细胞结合 -淀粉样蛋白(A)，并在A沉积部位聚集，包括老年斑。小胶质细胞相互作用 用A促进慢性炎症反应，其特征是产生促炎作用 细胞因子和趋化因子，活性氧和氮物种，以及补体蛋白。这是无菌的 炎症由A持续激活的小胶质细胞维持，并导致神经元变性 并增加A的沉积，从而促进疾病的进展。结合A的受体 A触发的促进慢性炎症的信号通路还不完全清楚。 我们的长期目标是确定A和A激活小胶质细胞的分子机制 这些通路在AD发病机制中的作用。我们假设Toll样受体(TLR)是一种 进化上古老的模式识别受体家族，检测微生物配体，启动和 维持对A的小胶质细胞炎症反应。这一假说是基于初步发现。 靶向缺失TLR信号转接子MyD88可消除小胶质细胞炎症反应 到A的体外和体内实验。在这项提案中，我们将定义TLRs和共同受体负责 启动这一信号，它们对小胶质细胞炎症反应的影响以及对 疾病。具体地说，我们将(1)定义TLR连接和信号在小胶质细胞反应中的作用 A在体外，(2)确定A辅助受体在促进TLR信号转导中的作用，以及(3)确定 A-TLR信号在体内对阿尔茨海默病病理的影响理解机制(S) 小胶质细胞与A的相互作用以及识别参与这些相互作用的受体将提供 对这些细胞在阿尔茨海默病发病机制中的作用有价值的见解，并可能确定治疗方法 阿尔茨海默病的靶点是促进小胶质细胞清除A，同时降低其神经毒性作用。

Microglia are the principal innate immune cells of the brain. In Alzheimer's disease (AD) these cells bind -amyloid (A) and accumulate at sites of A deposition, including senile plaques. Microglial interactions with A 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 A and leads to neuronal degeneration and increased A deposition and therefore promotes disease progression. The receptors that bind A and the signaling pathways triggered by A that promote chronic inflammation are not fully understood. Our long-term goals are to identify the molecular mechanisms of microglial activation by A 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 A. This hypothesis is based on preliminary findings that targeted deletion of the TLR signaling adaptor MyD88 abrogates microglial inflammatory responses to A in vitro and in vivo. In this proposal, we will define the TLRs and co-receptors responsible for initiating this signalling, 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 A in vitro, (2) Determine the role of A co-receptors in facilitating TLR signaling, and (3) Determine the impact of A-TLR signaling on Alzheimer's disease pathology in vivo. Understanding the mechanism(s) of microglial interactions with A 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 A while downregulating their neurotoxic effects.