Investigating the interactions between viral infection, Tau pathology, and neuroinflammation

项目摘要 越来越多的证据表明，神经免疫系统是阿尔茨海默病(AD)的主要因素。 增加神经炎症的环境因素，包括病毒感染，与AD的风险相关； 然而，微生物感染促进阿尔茨海默病的机制尚不清楚。广告的定义是 两种标志性病理的存在--由聚集的淀粉样β蛋白组成的细胞外老年斑 多肽(Aβ)与细胞内由过度磷酸化的微管组成的神经原纤维缠结 相关蛋白tau。最近的研究表明，Aβ可能是一种抗菌肽，其中 它的聚集可以通过将其捕获在细胞外空间来限制微生物感染。我们假设 作为一种细胞内蛋白，Tau可以作为一种抗菌肽来对抗病毒，病毒是细胞内专有的 病原体。我们的初步数据显示，在脑部接种一株减毒的韦斯特病毒后 尼罗河病毒，昆津病毒(KUNV)，Tau被过度磷酸化并聚集。此外，转基因 表达高水平易于聚集的Tau的小鼠显示其大脑中的病毒负担减少。在这里我们 建议用一只小鼠研究病毒感染、Tau病理和神经炎症之间的相互作用 脑炎KUNV感染模型的建立。目标1将确定病毒感染是否通过以下方式增加Tau病理 测量聚集、磷酸化和截断。目标2将评估Tau聚合对以下方面的影响 病毒复制以及Tau是否与病毒成分直接相互作用。目标3将检查Tau的效果 病毒感染后神经炎性反应的病理学研究。总之，这些实验将决定 病毒感染是否影响Tau病理的发展及Tau病理的调节作用 对病毒感染的神经免疫反应。这个项目的成功完成将建立一个机械的 阿尔茨海默病和病毒病原体之间的联系。

Project Summary Increasing evidence points to the neuroimmune system as a primary contributor to Alzheimer’s disease (AD). Environmental factors that increase neuroinflammation, including viral infections, correlate with risk of AD; however, the mechanisms by which microbial infections promote AD are not well understood. AD is defined by the presence of two hallmark pathologies—extracellular senile plaques composed of aggregated amyloid beta peptide (Aβ) and intracellular neurofibrillary tangles composed of the hyperphosphorylated microtubule associated protein tau. Recent studies have suggested that Aβ may act as an antimicrobial peptide, in which its aggregation can restrict microbial infection by trapping it in the extracellular space. We hypothesize that as an intracellular protein, Tau may act as an antimicrobial peptide against viruses, which are obligate intracellular pathogens. Our preliminary data shows that following intracranial inoculation with an attenuated strain of West Nile virus, Kunjin virus (KUNV), Tau becomes hyperphosphorylated and aggregates. Furthermore, transgenic mice expressing elevated levels of aggregation-prone Tau show reduced viral burden in their brains. Here we propose to study the interactions between viral infection, Tau pathology, and neuroinflammation using a murine model of encephalitic KUNV infection. Aim 1 will determine whether viral infection increases Tau pathology by measuring aggregation, phosphorylation, and truncation. Aim 2 will assess the impact of Tau aggregation on viral replication and whether Tau interacts directly with viral components. Aim 3 will examine the effect of Tau pathology on the neuroinflammatory response to viral infection. Together, these experiments will determine whether viral infection impacts the development of Tau pathology and the role of Tau pathology in modulating the neuroimmune response to viral infection. Successful completion of this project will establish a mechanistic link between AD and viral pathogens.