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

研究病毒感染、Tau 病理学和神经炎症之间的相互作用

基本信息

批准号：
10746267
负责人：
Kristen Emily Funk
金额：
$ 128.1万
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：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746267
关键词：
Acceleration Acute Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Attenuated Brain Cell Culture System Data Deposition Development Environment Environmental Risk Factor Exhibits Exposure to Extracellular Space Flow Cytometry Genes Goals Human Immune response Impaired cognition Infection Inflammation Inflammatory Response Kunjin virus Link MAPT gene Measures Modeling Molecular Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuroimmune Neuroimmune system Neurons Pathogenesis Pathology Pattern Phosphorylation Phosphotransferases Positioning Attribute Process Productivity Proteins Research Risk Risk Factors Role Senile Plaques System Testing Transgenic Mice Transgenic Organisms Viral Viral Encephalitis Viral Load result Virus Virus Diseases Virus Replication West Nile virus abeta accumulation abeta deposition antimicrobial peptide cytokine epidemiologic data epidemiology study experimental study extracellular hyperphosphorylated tau in vivo insight microbial mouse model neuroinflammation neuron loss neurotropic overexpression pathogen pathogenic bacteria pathogenic virus protein aggregation response tau Proteins tau aggregation tau interaction tau-1 transcriptome sequencing

项目摘要

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.

项目概要越来越多的证据表明神经免疫系统是阿尔茨海默病 (AD) 的主要原因。增加神经炎症的环境因素（包括病毒感染）与 AD 风险相关；然而，微生物感染促进 AD 的机制尚不清楚。存在两种标志性病变——由聚集的β淀粉样蛋白组成的细胞外老年斑肽（Aβ）和由过度磷酸化微管组成的细胞内神经原纤维缠结最近的研究表明，Aβ 可能作为一种抗菌肽，其中它的聚集可以通过将微生物捕获在细胞外空间来限制微生物感染。 Tau 是一种细胞内蛋白，可作为抗病毒的抗菌肽，而病毒是细胞内专性的我们的初步数据表明，颅内接种了West 减毒株。尼罗河病毒、昆金病毒 (KUNV)、Tau 蛋白过度磷酸化并聚集，而且是转基因的。表达高水平易聚集 Tau 蛋白的小鼠大脑中的病毒负荷减少。提议使用小鼠研究病毒感染、Tau 病理学和神经炎症之间的相互作用脑炎 KUNV 感染模型的目标 1 将通过以下方式确定病毒感染是否会增加 Tau 病理学。测量聚集、磷酸化和截短目标 2 将评估 Tau 聚集对的影响。病毒复制以及 Tau 是否直接与病毒成分相互作用，Aim 3 将检查 Tau 的作用。这些实验将共同确定病毒感染的神经炎症反应的病理学。病毒感染是否会影响 Tau 病理学的发展以及 Tau 病理学在调节中的作用对病毒感染的神经免疫反应的成功完成将建立一个机制。 AD 和病毒病原体之间的联系。