Microglial Hv1 Proton Channel as a Mediator of Environmentally-Induced Neuroinflammation and Neurodegeneration

摘要 神经炎症是导致神经退行性疾病的驱动力，包括帕金森病和帕金森病。 阿尔茨海默病（AD）和额颞叶痴呆（FTD）。小胶质细胞是大脑的主要免疫细胞 并且是感染、毒性损伤和聚集蛋白质的第一反应者， 神经炎症和神经退化。包括NLRP 3在内的小胶质细胞炎症反应 炎性小体激活，已被证明与AD显著相关。百草枯（PQ）是一种 常用的除草剂和PQ诱导的神经变性与小胶质细胞的激活紧密相关 并且似乎需要引发小胶质细胞反应。因此，调节小胶质细胞的因素 炎症反应可导致神经保护并减缓神经变性疾病的进展。 作为母公司资助的一部分，我们收集的初步数据表明，PQ暴露会导致启动， 原代小胶质细胞和野生型小鼠中NLRP 3炎性体的活化。此外，PQ暴露导致 增加的tau过度磷酸化在NLRP 3敲除小鼠中被消除。这项建议旨在测试 假设PQ暴露通过NLRP 3加速tau病理学的起始和进展 炎性小体，导致增强的tau病理学。

Abstract Neuroinflammation is a driving force contributing to neurodegenerative diseases, including Parkinson's and Alzheimer's disease (AD) and frontotemporal dementia (FTD). Microglia are the primary immune cell of the brain and are among the first responders to infection, toxic insult and aggregated proteins and contribute significantly to neuroinflammation and neurodegeneration. The microglial inflammatory response, including NLRP3 inflammasome activation, has been demonstrated to be significantly associated with AD. Paraquat (PQ) is a commonly used herbicide and PQ-induced neurodegeneration is tightly coupled to the activation of microglia and appears to require priming of the microglial response. Therefore, factors that modulate the microglial inflammatory response could lead to neuroprotection and slow the progression of neurodegenerative diseases. Our preliminary data collected as part of the parent grant demonstrate that PQ exposure leads to priming and activation of the NLRP3 inflammasome in primary microglia and wild type mice. Further, PQ exposure leads to increased tau hyperphosphorylation that is abolished in NLRP3 knockout mice. This proposal seeks to test the hypothesis that PQ exposure accelerates the initiation and progression of tau pathology through the NLRP3 inflammasome, leading to enhanced tau pathology.