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

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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.