Toll-Like Receptor Signaling in Alzheimer's Disease

描述（申请人提供）：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沉积部位积聚，包括老年斑。小胶质细胞与A¿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、活性氧和活性氮以及补体蛋白。这种无菌炎症通过A¿持续激活小胶质细胞来维持，并导致神经元变性和A¿沉积增加，从而促进疾病进展。结合A¿的受体和由A¿引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A¿激活小胶质细胞的分子机制以及这些途径对阿尔茨海默病发病机制的影响。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，用于检测微生物配体，启动并维持小胶质细胞对A¿的炎症反应。这一假设是基于初步发现，在体外和体内，靶向删除TLR信号适配器MyD88可以消除小胶质细胞对A¿的炎症反应。在本提案中，我们将定义负责启动该信号的tlr和共受体，它们对小胶质细胞炎症反应的影响及其对疾病的影响。具体而言，我们将(1)确定TLR连接和信号传导在体外小胶质细胞对A¿的反应中的作用，(2)确定A¿共受体在促进TLR信号传导中的作用，以及(3)确定A¿-TLR信号传导对阿尔茨海默病病理的影响。了解小胶质细胞与A¿相互作用的机制并确定参与这些相互作用的受体将为这些细胞在阿尔茨海默病发病机制中的作用提供有价值的见解，并可能确定阿尔茨海默病的治疗靶点，以促进小胶质细胞对A¿的清除，同时下调其神经毒性作用。公共卫生相关性：在阿尔茨海默病（AD）中，小胶质细胞与-淀粉样蛋白肽的相互作用促进慢性无菌炎症，导致神经元变性、-淀粉样蛋白沉积增加和疾病进展。了解小胶质细胞与淀粉样蛋白相互作用的机制，识别参与炎症的受体，将为这些细胞在阿尔茨海默病发病机制中的作用提供有价值的见解，并可能通过促进小胶质细胞清除淀粉样蛋白的能力，同时下调其有害和神经毒性作用，从而使小胶质细胞成为阿尔茨海默病的治疗靶点。

DESCRIPTION (provided by applicant): 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 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 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. PUBLIC HEALTH RELEVANCE: In Alzheimer's disease (AD), microglial interactions with ¿-amyloid peptide promote chronic sterile inflammation that leads to neuronal degeneration, increased ¿-amyloid deposition and disease progression. Understanding the mechanisms of microglial interactions with ¿-amyloid and identifying the receptors involved in promoting inflammation will provide valuable insight into the role of these cells in the pathogenesis of AD and possibly allow the use of microglia as therapeutic targets for AD by promoting their ability to clear ¿-amyloid while downregulating their harmful and neurotoxic effects.