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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.

项目摘要/摘要