Neurotropic Viral Infection in CNS Aging and Alzheimer's Disease

项目摘要 据估计，阿尔茨海默病（AD）目前影响着530万美国人，预计在2010年将继续上升。 未来十年神经炎症越来越多地被认为是导致中枢神经系统疾病的原因。 系统（CNS），包括AD。小胶质细胞表面受体TREM 2最近从两个 独立的全基因组关联研究有助于发展AD的风险，以及先前的研究 提示感染负荷可能参与AD的发病机制。我假设病毒 脑炎可能会增强炎症反应，加速中枢神经系统老化的正常过程， 有助于AD病理学的发展。这个为期五年的项目有三个具体目标， 尼罗河病毒（WNV）神经侵袭性疾病作为病毒性脑炎的模型。在K99指导阶段， 该项目的目标1将确定由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TREM 2-/-小鼠模型观察脑炎。我假设病毒性脑炎会引发神经炎症 通过端粒缩短和炎症反应加速小胶质细胞复制性衰老的过程 细胞因子表达由于TREM 2在感知环境损害相关分子中至关重要， 模式，我们预计TREM 2-/-小胶质细胞在响应神经元损伤方面将不太有效。 病毒性脑炎导致中枢神经系统老化。目标2也是在K99指导阶段， 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。数据来自Klein 实验室证明IL-1受体1（IL-1 R1）信号传导对于急性嗜神经病毒性脑膜炎患者存活是必需的， 感染然而，包括IL-1和IL-8在内的炎性细胞因子通过IL-1 R1信号传导上调， 通过DNA损伤促进神经元衰老。本实验旨在研究IL-1 R1在肿瘤细胞中的作用。 使用IL-1 R1-/-小鼠和体外研究从WNV脑炎恢复后和神经元老化期间的信号传导 原代神经元培养模型。在该项目的R 00独立阶段，Aim 3将探索 病毒性脑炎对病理性tau积累影响。AD定义为蛋白质沉积 由Aβ和tau组成。已知Aβ刺激慢性炎症;然而，关于其作用知之甚少。 在神经炎症级联反应中错误折叠的tau蛋白，甚至更少有人知道神经炎症是如何发生的。 可以促进tau沉积。我假设病毒引起的急性神经炎症 脑炎可使个体易患AD病理。本目标的实验将确定 病毒性脑炎是否会增加携带Mapt P301 L突变的转基因小鼠的发病率， 开发tau病理学，鉴定tau聚集体对初级小胶质细胞衰老过程的影响，以及 确定IL-1β是否影响来自Mapt P301 L的原代神经元培养物中的tau聚集倾向 胚胎小鼠这些研究将使人们对病毒性脑炎的影响有新的认识， 中枢神经系统的衰老和AD的发展。

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.