Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease

中枢神经系统衰老和阿尔茨海默氏病中的神经病毒感染

基本信息

批准号：
10160734
负责人：
Kristen Emily Funk
金额：
$ 24.08万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10160734
关键词：
Acute Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology American Amyloid beta-Protein Antigen Presentation Award Behavioral Binding Brain Cell Aging Cell Surface Receptors Central Nervous System Diseases Chronic Cognitive DNA Damage Data Dementia Deposition Development Disease Embryo Encephalopathies Epidemic Epigenetic Process Event Gene Expression Genes Genetic Genetic Polymorphism Goals IL8 gene Immune Impaired cognition In Vitro Individual Infection Infectious Agent Inflammation Inflammatory Innate Immune System Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Lead Ligands Longevity MAPT gene Maintenance Mediating Memory Loss Mentors Microglia Mitotic Modeling Modification Molecular Morbidity - disease rate Mus Mutation Nerve Degeneration Neuraxis Neuroimmune Neurons Pathogenesis Pathologic Pathology Pathway interactions Pattern Peripheral Phagocytosis Phase Process Proliferating Recovery Resolution Risk Risk Factors Role Scientist Signal Transduction Synapses TREM2 gene Telomere Shortening Training Transgenic Mice United States Up-Regulation Viral Viral Encephalitis Virus Diseases West Nile Encephalitis West Nile viral infection West Nile virus cytokine emerging human pathogen epidemiologic data experimental study functional decline genetic signature genome wide association study mortality mouse model multidisciplinary nervous system development neuroimmunology neuroinflammation neuron loss neurotropic novel novel therapeutics overexpression oxidative DNA damage receptor response self-renewal senescence tau Proteins tau aggregation virology

项目摘要

Project Summary Alzheimer's disease (AD) is estimated to affect 5.3 million Americans currently and is expected to rise over the next decade. Neuroinflammation is increasingly recognized as contributing to disorders of the central nervous system (CNS) including AD. Microglial cell surface receptor TREM2 was recently identified from two independent genome-wide association studies to contribute to the risk of developing AD, and previous studies suggested that infectious burden may contribute to the etiopathogenesis of AD. I hypothesize that viral encephalitis may enhance inflammatory events that accelerate the normal processes of CNS aging and contribute to the development of AD pathology. This five-year project has three specific aims that use West Nile virus (WNV) neuroinvasive disease as a model of viral encephalitis. During the K99 mentored phase of this project, Aim 1 will identify mechanisms of microglial-mediated aging processes triggered by WNV encephalitis using a TREM2-/- mouse model. I hypothesize that viral encephalitis triggers neuroinflammatory processes that accelerate replicative senescence in microglia via telomere shortening and inflammatory cytokine expression. Because TREM2 is critical in sensing environmental damage associated molecular patterns, we expect that TREM2-/- microglia will be will be less effective in responding to neuronal damage following viral encephalitis causing increased CNS aging. Aim 2, also during the K99 mentored phase, will identify mechanisms of neuron-mediated aging processes triggered by WNV encephalitis. Data from the Klein lab demonstrate that IL-1 receptor 1 (IL-1R1) signaling is essential for survival from acute neurotropic viral infection. However, inflammatory cytokines including IL-1 and IL-8, which are upregulated via IL-1R1 signaling, contribute to neuronal senescence via DNA damage. Experiments in this Aim will examine the role of IL-1R1 signaling following recovery from WNV encephalitis and during neuronal aging using IL-1R1-/- mice and in vitro primary neuron culture models. During the R00 independent phase of this project, Aim 3 will explore the impact of viral encephalitis on pathological tau accumulation. AD is defined by proteinaceous deposits composed of Aβ and tau. Aβ is known to stimulate chronic inflammation; however, less is known about the role of misfolded tau in the neuroinflammatory cascade, and even less is known is about how neuroinflammation can contribute to tau deposition. I hypothesize that an acute episode of neuroinflammation caused by viral encephalitis may predispose an individual to develop AD pathology. Experiments in this Aim will determine whether viral encephalitis increases the rate at which transgenic mice harboring the Mapt P301L mutation develop tau pathology, identify the impact of tau aggregates on the aging processes in primary microglia, and determine whether IL-1β impacts tau aggregation propensity in primary neurons cultures from Mapt P301L embryonic mice. These studies will give new understanding of the impact of viral encephalitis to processes of aging in the CNS and the development of AD.

项目概要据估计，目前有 530 万美国人患有阿尔茨海默病 (AD)，并且预计这一数字将在未来十年，人们越来越认识到神经炎症会导致中枢神经系统疾病。包括 AD 在内的小胶质细胞表面受体 TREM2 的系统 (CNS) 最近从两个中被鉴定出来。独立的全基因组关联研究有助于增加患 AD 的风险，以及之前的研究表明感染负担可能导致 AD 的发病机制。脑炎可能会增强炎症事件，从而加速中枢神经系统衰老的正常过程为 AD 病理学的发展做出贡献这个为期五年的项目有三个利用 West 的具体目标。尼罗河病毒 (WNV) 神经侵袭性疾病作为病毒性脑炎的 K99 指导阶段。该项目的目标 1 将确定 WNV 触发的小胶质细胞介导的衰老过程的机制我使用 TREM2-/- 小鼠模型发现病毒性脑炎会引发神经炎症。通过端粒缩短和炎症加速小胶质细胞复制衰老的过程因为 TREM2 在感知环境损伤相关分子中至关重要。模式，我们预计 TREM2-/- 小胶质细胞对神经元损伤的反应效果会较差病毒性脑炎导致中枢神经系统老化加剧后，目标 2（也在 K99 指导阶段）将实现。确定由 WNV 脑炎引发的神经元介导的衰老过程的机制。数据来自 Klein。实验室证明 IL-1 受体 1 (IL-1R1) 信号对于急性嗜神经病毒的生存至关重要然而，炎症细胞因子（包括 IL-1 和 IL-8）通过 IL-1R1 信号传导上调，通过 DNA 损伤导致神经元衰老。该目的的实验将检查 IL-1R1 的作用。使用 IL-1R1-/- 小鼠和体外实验研究西尼罗河病毒脑炎恢复后和神经衰老期间的信号传导在该项目的 R00 独立阶段，Aim 3 将探索初级神经元培养模型。病毒性脑炎对 AD 病理性 tau 积累的影响是通过蛋白质沉积来定义的。由 Aβ 和 tau 蛋白组成，已知会刺激慢性炎症；但对其作用知之甚少。错误折叠的 tau 蛋白在神经炎症级联反应中的作用，而关于神经炎症是如何发生的，我们知之甚少。可能会导致 tau 沉积脑炎可能使个体易患阿尔茨海默病 (AD) 病理，该目的的实验将确定。病毒性脑炎是否会增加携带 Mapt P301L 突变的转基因小鼠的发生率开发 tau 病理学，确定 tau 聚集体对原代小胶质细胞衰老过程的影响，以及确定 IL-1β 是否影响 Mapt P301L 原代神经元培养物中 tau 聚集倾向这些研究将为病毒性脑炎对病毒性脑炎过程的影响提供新的认识。中枢神经系统的衰老和 AD 的发展。