Role of MyD88 signaling in systemic inflammation and Alzheimer disease

项目摘要/摘要 阿尔茨海默病(AD)患者的主要病理改变是细胞外淀粉样蛋白β(Aβ) 脑实质中的沉积(淀粉样斑块)和过度磷酸化的tau的异常聚集 脑神经元中的蛋白质(神经原纤维缠结，NFT)。淀粉样斑块和神经营养不良伴发慢性 以小胶质细胞激活和细胞因子水平升高为特征的炎症。除了一小部分 早发性家族性AD病例，绝大多数AD病例病因不明且令人满意 目前尚无治疗和预防阿尔茨海默病的措施。因此，迫切需要确定 分子机制增加了绝大多数AD病例的风险，并开发了预防和 治疗措施。全身炎症促进AD进展，甚至启动小胶质细胞激活 和神经退化。事实上，最近对晚发性阿尔茨海默病的遗传学研究已经确定了大约12个基因 在小胶质细胞中高表达并参与先天性免疫反应的风险变异体，突出了 免疫反应，特别是激活的小胶质细胞，在晚发性AD发病机制中的重要性。老龄化 是已知的AD的最大危险因素，以慢性全身炎症(炎症老化)为特征。 由某些细菌和病毒感染引起的全身炎症也是痴呆症的一个强烈的风险因素。 此外，我们的初步数据表明，NLRP3炎症小体通过MyD88信号被激活 中枢神经系统(CNS)小胶质细胞通路在AD发病机制中起重要作用。在AIM 1，我们将在AD小鼠模型中产生小胶质细胞特异性MyD88缺陷，并确定其 对Aβ和tau病理及认知功能的影响。我们进一步假设小胶质细胞MyD88信号 在加速脑Aβ和tau病理以及神经炎症方面起主导作用 通过慢性、全身性炎症，在AD小鼠模型衰老过程中。在目标2中，我们将确定 系统脂多糖治疗对脑及外周AD模型小鼠A-β和tau病理及认知功能的影响 免疫细胞特异性MyD88缺乏症。在目标3中，我们将确定内毒素的年龄和性别依赖效应 治疗NLRP3炎症体激活作为脑/小胶质细胞特异性和 外周免疫细胞特异性MyD88缺陷AD小鼠模型。我们的假设是，内毒素诱导 全身炎症通过MyD88信号导致小胶质细胞NLRP3炎症体激活，导致 阿尔茨海默病模型小鼠类AD病理生理学的恶化。长期目标是确定 小胶质细胞MyD88/NLRP3炎症信号在AD发病机制中的分子阐明 与全身炎症相关的AD风险增加的潜在机制并开发新的 AD的预防和治疗策略。

Project Summary / Abstract The main pathological changes found in patients with Alzheimer’s disease (AD) are extracellular amyloid β (Aβ) deposits in the brain parenchyma (amyloid plaques) and abnormal aggregates of hyperphosphorylated tau protein in brain neurons (neurofibrillary tangles, NFTs). Amyloid plaques and NFTs are accompanied with chronic inflammation characterized by activated microglia and increased levels of cytokines. Except a small subset of early-onset familial AD cases, the causes for the vast majority of AD cases are unknown and satisfactory therapeutic and preventive measures for AD are unavailable. Therefore, an urgent need exists to identify the molecular mechanisms that increase the risk for the vast majority of AD cases and to develop the preventive and therapeutic measures. Systemic inflammation promotes AD progression and even initiates microglial activation and neurodegeneration. Indeed, recent genetic studies on late-onset AD have identified about a dozen genetic risk variants that are highly expressed in microglia and involved in innate immune responses, highlighting the importance of immune responses, particularly activated microglia, in the pathogenesis of late-onset AD. Aging is the largest known risk factor for AD and is characterized by chronic, systemic inflammation (inflamm-aging). Systemic inflammation caused by certain bacterial and viral infections is a strong risk factor of dementia, also. Additionally, our preliminary data indicate that activation of NLRP3 inflammasome through the MyD88 signaling pathway in microglia in the central nervous system (CNS) plays essential roles in the AD pathogenesis. In Aim 1, we will produce a microglia specific MyD88 deficiency in AD mouse models during aging and determine their effect on Aβ and tau pathology and cognitive function. We further hypothesize that microglial MyD88 signaling plays a predominant role in accelerating brain Aβ and tau pathology and neuroinflammation, which are induced by chronic, systemic inflammation, in AD mouse models during aging. In Aim 2, we will determine the effects of systemic LPS treatment on Aβ and tau pathology and cognition in AD mouse models with brain and peripheral immune cell-specific MyD88 deficiency. In Aim 3, we will determine the age and sex dependent effects of LPS treatment on NLRP3 inflammasome activation as disease mechanisms in the brain/microglia-specific and peripheral immune cell-specific MyD88 deficient AD mouse models. Our hypothesis is that LPS-induced systemic inflammation causes NLRP3 inflammasome activation in microglia via MyD88 signaling, leading to exacerbation of AD-like pathophysiology in AD mouse models. The long term goals are to determine the role of microglial MyD88/NLRP3 inflammasome signaling in the AD pathogenesis, to elucidate the molecular mechanism underlying the increased AD risk associated with systemic inflammation and to develop new preventive and therapeutic strategies for AD.