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

小胶质细胞 Hv1 质子通道作为环境诱发的神经炎症和神经变性的介质

• 批准号: 10714415
• 负责人: Jason R Richardson
• 金额: $ 36.88万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-04 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10714415
• 关键词: Acceleration; Alzheimer' s Disease; Coupled; Data; Environment; Frontotemporal Dementia; Herbicides; Immune; Infection; Inflammasome; Inflammatory Response; Knockout Mice; Link; Mediator; Microglia; Nerve Degeneration; Neurodegenerative Disorders; Paraquat; Parkinson Disease; Pathology; Pathway interactions; Protons; Role; Testing; Wild Type Mouse; brain cell; driving force; first responder; hyperphosphorylated tau; neuroinflammation; neuroprotection; parent grant; protein aggregation; response; tau Proteins

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.

抽象的 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 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 是对感染、毒性损伤和聚集蛋白的第一反应者，并做出了重大贡献 神经炎症和神经变性。小胶质细胞炎症反应，包括 NLRP3 炎症小体激活已被证明与 AD 显着相关。百草枯 (PQ) 是一种 常用除草剂和 PQ 诱导的神经变性与小胶质细胞的激活紧密相关 并且似乎需要启动小胶质细胞反应。因此，调节小胶质细胞的因素 炎症反应可能会导致神经保护并减缓神经退行性疾病的进展。 我们作为家长资助的一部分收集的初步数据表明，PQ 暴露会导致启动和 原代小胶质细胞和野生型小鼠中 NLRP3 炎性体的激活。此外，PQ 暴露会导致 tau 过度磷酸化增加，但在 NLRP3 敲除小鼠中被消除。该提案旨在测试 假设 PQ 暴露通过 NLRP3 加速 tau 病理学的发生和进展 炎症小体，导致 tau 病理学增强。