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

基本信息

批准号：
10611489
负责人：
Ken-ichiro Fukuchi
金额：
$ 50.13万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
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/10611489
关键词：
3xTg-AD mouse Acceleration Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-Protein Animal Model Bacterial Infections Binding Bone Marrow Brain CASP1 gene Cell Death Cells Central Nervous System Chronic Cognition Cytoplasmic Protein Data Dementia Deposition Development Disease Disease Progression Early Onset Familial Alzheimer&apos s Disease Etiology Event Functional disorder Genetic Risk Genetic study Goals IL18 gene Immune Immune response In Vitro Inflammaging Inflammasome Inflammation Inflammatory Innate Immune Response Interleukin Activation Interleukin-1 beta Late Onset Alzheimer Disease MYD88 deficiency Measures Mediating Microglia Molecular Multiprotein Complexes Nerve Degeneration 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 glial activation hyperphosphorylated tau in vivo marenostrin mild cognitive impairment mouse model neuroinflammation neuron loss neuropathology protein complex reconstitution risk variant sensor sex systemic inflammatory response tau Proteins tau aggregation tau-1

项目摘要

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.

项目概要/摘要阿尔茨海默病（AD）患者发现的主要病理变化是细胞外淀粉样蛋白（Aβ）脑实质沉积物（淀粉样斑块）和过度磷酸化 tau 蛋白的异常聚集大脑神经元中的蛋白质（神经原纤维缠结，NFT）伴随着慢性淀粉样斑块和NFT。炎症的特征是小胶质细胞激活和细胞因子水平升高，一小部分除外。早发性家族性 AD 病例，绝大多数 AD 病例的病因不明，且大多数情况令人满意因此，目前尚无 AD 的治疗和预防措施。增加绝大多数 AD 病例风险的分子机制，并制定预防和预防措施治疗措施会促进 AD 进展，甚至启动小胶质细胞激活。事实上，最近关于迟发性 AD 的遗传学研究已经确定了大约十几种遗传因素。在小胶质细胞中高度表达并参与先天免疫反应的风险变异，强调了免疫反应，特别是活化的小胶质细胞，在迟发性 AD 发病机制中的重要性。是 AD 最大的已知危险因素，其特点是慢性、全身性炎症（炎症衰老）。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重要危险因素。此外，我们的初步数据表明，NLRP3 炎症小体通过 MyD88 信号传导激活中枢神经系统 (CNS) 中的小胶质细胞通路在 AD 发病机制中发挥着重要作用。 1、我们将在衰老过程中制作小胶质细胞特异性MyD88缺陷的AD小鼠模型，并确定其我们进一步研究了小胶质细胞 MyD88 信号传导对 Aβ 和 tau 病理学和认知功能的影响。在加速大脑 Aβ 和 tau 病理学以及神经炎症方面起主要作用，这些都是由在目标 2 中，我们将确定衰老过程中 AD 小鼠模型中慢性、全身性炎症的影响。全身 LPS 治疗对大脑和外周 AD 小鼠模型 Aβ 和 tau 病理学和认知的影响在目标 3 中，我们将确定 LPS 的年龄和性别依赖性影响。 NLRP3 炎症小体激活作为大脑/小胶质细胞特异性疾病机制的治疗外周免疫细胞特异性 MyD88 缺陷的 AD 小鼠模型我们的假设是 LPS 诱导的。全身炎症通过 MyD88 信号传导导致小胶质细胞中 NLRP3 炎性体激活，从而导致 AD 小鼠模型中 AD 样病理生理学的恶化长期目标是确定 AD 样病理生理学的作用。 AD 发病机制中的小胶质细胞 MyD88/NLRP3 炎性体信号传导，以阐明 AD 发病机制中的分子机制与全身炎症相关的 AD 风险增加的潜在机制，并开发新的 AD 的预防和治疗策略。