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

• 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
• 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' s Disease; Alzheimer' 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

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.

项目摘要 据估计，阿尔茨海默病(AD)目前影响着530万美国人，预计未来几年还会上升 下一个十年。神经炎越来越被认为是导致中枢神经紊乱的原因。 系统(CNS)，包括AD。小胶质细胞表面受体TREM2最近从两个 与阿尔茨海默病发病风险相关的独立全基因组研究和先前的研究 提示感染性负担可能参与了AD的发病机制。我假设病毒感染了 脑炎可能会增强炎症事件，从而加速中枢神经系统的正常衰老和 为AD病理学的发展作出贡献。这个为期五年的项目有三个具体目标，利用WESTER 尼罗河病毒(WNV)神经侵袭性疾病作为病毒性脑炎的模型。在K99指导阶段 该项目的目标1将确定西尼罗河病毒引发的小胶质细胞介导的衰老过程的机制 使用TREM2-/-小鼠模型制作脑炎模型。我假设病毒性脑炎会引发神经炎 通过端粒缩短和炎症加速小胶质细胞复制衰老的过程 细胞因子的表达。因为TREM2在感知环境损害相关分子方面是至关重要的 我们预计，TREM2-/-小胶质细胞在应对神经元损伤方面将不那么有效 病毒性脑炎导致中枢神经系统老化加剧。目标2，也是在K99指导阶段，将 确定由西尼罗河病毒脑炎引发的神经元介导的衰老过程的机制。来自克莱恩的数据 实验室研究表明，IL-1受体1(IL-1R1)信号对急性嗜神经性病毒的存活至关重要 感染。然而，包括IL-1和IL-8在内的炎性细胞因子通过IL-1R1信号上调， 通过DNA损伤导致神经元衰老。以此为目的的实验将检验IL-1R1的作用 使用IL-1R1-/-小鼠和体外培养的WNV脑炎恢复后和神经元老化过程中的信号转导 原代神经元培养模型。在该项目的R00独立阶段，Aim 3将探索 病毒性脑炎对病理性tau蓄积的影响。AD由蛋白质沉积来定义 由β和tau组成。众所周知，β可以刺激慢性炎症；然而，人们对其作用知之甚少 错误折叠的tau在神经炎性级联反应中的作用，而关于神经炎性反应是如何发生的更是鲜为人知 可以促进牛磺酸的沉积。我假设由病毒引起的急性神经炎发作 脑炎可能使个体易患上AD病理。这一目标的实验将确定 病毒性脑炎是否会增加携带MAPT P301L突变的转基因小鼠的比率 发展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原代培养神经元的tau聚集倾向 胚胎老鼠。这些研究将使人们对病毒性脑炎对脑出血过程的影响有新的认识。 中枢神经系统衰老与阿尔茨海默病的发展。