Role of MyD88 signaling in systemic inflammation and Alzheimer disease

MyD88 信号在全身炎症和阿尔茨海默病中的作用

• 批准号: 10456872
• 负责人: Ken-ichiro Fukuchi
• 金额: $ 46.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456872
• 关键词: 3xTg-AD mouse; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Animal Model; Bacterial Infections; Binding; Bone Marrow; Brain; CASP1 gene; Cell Death; Cells; Chronic; Cognition; Cytoplasmic Protein; Data; Deposition; Development; Disease; Disease Progression; Early Onset Familial Alzheimer' s Disease; Etiology; Event; Functional disorder; Genetic Risk; Genetic study; Goals; Immune; Immune response; In Vitro; Inflammaging; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Interleukin Activation; Interleukin-1 beta; Interleukin-18; Late Onset Alzheimer Disease; MYD88 deficiency; Measures; Mediating; Microglia; Molecular; Multiprotein Complexes; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Play; Preventive; Preventive measure; Production; Proteins; Risk; Role; Senile Plaques; Signal Pathway; Signal Transduction; Synapses; System; Therapeutic; Virus Diseases; abeta accumulation; brain parenchyma; cognitive function; cytokine; dementia risk; extracellular; hyperphosphorylated tau; in vivo; marenostrin; mild cognitive impairment; mouse model; neuroinflammation; neuron loss; protein complex; reconstitution; risk variant; sensor; sex; systemic inflammatory response; tau Proteins; tau aggregation; tau phosphorylation

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.

项目摘要 /摘要 阿尔茨海默氏病（AD）患者发现的主要病理变化是细胞外淀粉样蛋白β（Aβ） 脑薄壁组织中的沉积物（淀粉样蛋白斑块）和高磷酸化tau的异常聚集体 脑神经元中的蛋白质（神经原纤维缠结，NFTS）。淀粉样斑块和NFT伴有慢性 炎症为特征是活化的小胶质细胞和细胞因子水平升高。除了一小部分 早期发作的家庭广告案例，绝大多数AD案件的原因是未知和满意的工厂 AD的治疗和预防措施不可用。因此，迫切需要确定 分子机制增加了绝大多数AD病例并发展预防和 治疗措施。全身感染促进AD进展，甚至启动小胶质激活 和神经变性。实际上，最近关于晚期AD的遗传研究已经鉴定出大约十几个遗传 在小胶质细胞中高度表达并参与先天免疫调查的风险变体，突出显示 免疫反应，特别是活化的小胶质细胞的重要性，在晚期AD的发病机理中。老化 是AD的最大危险因素，其特征是慢性全身性炎症（炎症）。 某些细菌和病毒感染引起的全身感染也是痴呆症的强大危险因素。 此外，我们的初步数据表明通过MyD88信号激活NLRP3炎症体 中枢神经系统（CNS）中小胶质细胞的途径在AD发病机理中起着重要的作用。目标 1，我们将在衰老期间在AD鼠标模型中产生特定于AD鼠标的MyD88缺乏症并确定其 对Aβ和TAU病理和认知功能的影响。我们进一步假设小胶质MyD88信号传导 在加速脑Aβ和TAU病理学和神经炎症中起主要作用，这是诱导的 在衰老期间，通过慢性，全身炎症，在AD小鼠模型中。在AIM 2中，我们将确定 具有大脑和周围的AD小鼠模型中Aβ和TAU病理学和认知的全身性LPS处理 免疫细胞特异性MYD88缺陷。在AIM 3中，我们将确定LPS的年龄和性依赖性影响 NLRP3炎性体激活作为脑/小胶质细胞特异性的疾病机制和 外周免疫球特异性MYD88缺陷AD鼠标模型。我们的假设是LPS诱导的 全身性炎症会通过MyD88信号传导在小胶质细胞中引起NLRP3炎症体激活，从而导致 AD小鼠模型中AD样病理生理的加剧。长期目标是确定 AD发病机理中的小胶质细胞MyD88/NLRP3炎性体信号传导，以阐明分子 与全身感染相关的AD风险增加的机制并发展了新的 AD的预防和治疗策略。