The Neuroinflammatory Impact of Binge Ethanol Exposure in Aged Mice: A Role for NLRP3.

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PROJECT SUMMARY Forty percent of aged adults (>65 years of age) consume alcohol and the population of aged adults that participate in binge drinking is growing. Despite a concurrent increase in the number of age-related neurodegenerative diseases like Alzheimer's disease and related dementias, the effect binge drinking has on the aged brain and neurodegeneration is not well understood. Although dysregulated host immunity and heightened production of pro-inflammatory mediators are significant and independent contributors to both age- and alcohol-related neurodegeneration, the combined effect of alcohol and advanced age on neuroinflammation is not well characterized. Our preliminary data demonstrate that following binge ethanol exposure, the production of pro-inflammatory cytokines in the hippocampus is greater in aged mice compared to young. The goal of this proposal is to identify specific mechanisms leading to heightened neuroinflammatory responses to ethanol in the aged brain. Activation of both the NLRP3 inflammasome and microglia, the resident macrophages of the central nervous system, are critical factors leading to alcohol-induced neuroinflammation and injury in the young brain. Moreover, aging models have established NLRP3 and heightened microglia activation as central factors leading to amplified inflammatory responses and associated neuronal damage in the aged brain. The specific contribution of NLRP3 in driving enhanced neuroinflammatory responses to ethanol, including microglia activation, in advanced age has not yet been defined. It is our working hypothesis that relative to young, binge ethanol exposure leads to heightened activation of microglia, excessive neuroinflammation and associated neurodegeneration in the aged brain. Moreover, we hypothesize that these exaggerated responses to ethanol in advanced age are NLRP3 dependent. To test this, in Aim 1 we will comprehensively characterize the effect of binge ethanol exposure on neuroinflammation, neurodegeneration, and cognitive impairment in young and aged mice using multispectral imaging and behavioral assays. We will then define the role of NLRP3 as an important contributor for advanced age- and ethanol-related hippocampal damage by making use of NLRP3 knockout young and aged mice. In Aim 2, we will elucidate the cell-specific role of NLRP3 in primary microglia harvested from young and aged mice. We will characterize microglia phenotype after ex vivo ethanol exposure of primary microglia and take the novel approach to use the specific NLRP3 inhibitor, OLT1177, to alleviate ethanol-induced inflammation in primary microglia from the young and aged brain. Together, these studies will unveil how alcohol-misuse during aging may contribute to neurodegenerative disease pathogenesis and identify new therapeutic targets to prevent age- and alcohol-related neurodegeneration.