Aging, alcohol, and microglia dysfunction

Abstract The global population is aging rapidly, with an estimated 2.1 billion people aged 60 or over expected by 2050. Aging baby boomers are contributing to an increase in heavy alcohol consumption and alcohol use disorders (AUDs). Indeed, AUD rates have increased by 82.5% in those aged 65 and over, which exacerbates risk for cognitive decline, accelerated aging, dementia, and early death. Excessive alcohol intake in aged individuals likely dysregulates immune dynamics in brain. The neuroimmune system critically regulates cognitive and behavioral changes with aging – pathological inflammatory priming and/or reactivity occurs with neurodegenerative disorders and elicits cognitive decline. The main resident immune cell of the CNS, microglia, help maintain a healthy milieu by surveying for damage or infection; by responding to damage-related cues; and by phagocytosing dying cells and excess synapses. Microglia play key roles in alcohol-induced neuroinflammation and in aging-related neurotoxicity; however, little is known about how alcohol and aging intersect at the level of the neuroimmune system. Thus, here we propose that neuroinflammatory responses are dysregulated in the aged brain resulting in increased vulnerability to the neuropathological effects of heavy, alcohol exposure. We provide strong preliminary data demonstrating that heavy binge-like exposure to alcohol leads to substantial and progressive impairments in cognition and an altered neuroimmune environment. Our overall objective is to determine whether dysregulated neuroimmune, and particularly microglia, function is critical to this heightened age-associated damage following heavy, alcohol exposure. The central hypothesis of this proposal is that heavy alcohol exposure in aging produces delayed hippocampal neurodegeneration and cognitive deficits through impaired microglia phagocytic and inflammatory functions. The proposal addresses the following specific aims: First, characterize the interaction of aging and heavy, binge-like alcohol exposure on corticolimbic structure and function. Second, determine how aging and alcohol interact to induce changes in microglia phenotype and function following heavy, alcohol exposure. Third, interrogate the role of microglia dysfunction following alcohol in aged rats on corticolimbic structure and function. The third mechanism-focused aim will examine the precise role of microglia in contributing to damage in the aged brain in response to alcohol. The proposal is innovative in combining expertise in alcohol use disorders, aging, and neuroimmunology. It uses state-of-the-art approaches including ex vivo microglia functional assays, confocal microscopy and 3D cellular reconstructions, microglia depletion, and single cell RNA-sequencing to identify novel pathways perturbed by alcohol exposure in the aging system. This contribution will be significant as alcohol use is a growing concern in aged populations but an understudied area. The proposed studies will provide a mechanistic foundation to elucidate novel targets for therapeutic intervention to reduce alcohol-induced brain and cognitive/behavioral impairments and explore alcohol's acceleration of brain aging.