Adolescent Alcohol Abuse, PTSD and Alzheimer's Disease Administrative Supplement

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PROJECT SUMMARY/ABSTRACT Anxiety and depression co-occur in both alcohol use disorder (AUD) and Alzheimer’s disease, and both illnesses target the noradrenergic system and circuits in hippocampus and amygdala. This overlap in symptoms and impacted brain regions raise the question of shared mechanisms, and whether adolescent intermittent ethanol exposure can set the brain on a trajectory that makes it more susceptible to Alzheimer’s pathology and related dementia in aging. Conflicting literature shows light to moderate alcohol drinking may be protective, while others report increased risk, or no effect, of alcohol use and AD risk. Variable durations and intensity of alcohol use and measures of dementia likely contribute to the lack of a coherent understanding of the interactions of alcohol exposure and development of Alzheimer’s disease. Use of preclinical models and well controlled studies will provide a platform to understand possible overlapping mechanisms that can trigger AD following significant ethanol exposure during adolescence. Surprisingly, to date, extremely few preclinical studies have investigated the interaction between alcohol use and AD risk and disease progression. In support of the hypothesis that AUD augments AD pathology, a recent study using adolescent intermittent ethanol exposure (P25-55) in 3xFAD mice harboring three human AD mutations displayed increased Aβ1–42 accumulation in hippocampus, amygdala, and entorhinal cortex and pTau accumulation in hippocampus of adult females. These mice also experienced increased anxiety and learning and memory deficits. Importantly, pharmacologically blocking inflammation prevented both the pathological and behavioral changes. In another study in humanize pTau mutant mice, intermittent ethanol increased excitability of locus coeruleus (LC) noradrenergic neurons with a greatest effect in females. Our expertise in AUD, AD, sex differences and synaptic circuits skillfully and uniquely positions us to test the overarching hypothesis that adolescent intermittent ethanol accelerates AD pathology and synaptic dysfunction and shortens the period of prodromal AD. Aim 1 will test the hypothesis that AIE exposure accelerates accumulation of Ab and pTau and increases gliosis and neuronal and synaptic dysfunction during prodromal AD in adult TgF344-AD rats. Aim 2 will test the hypothesis that AIE exposure accelerates deficits in learning and memory, increases anxiety, and impaires fear extinction during the prodromal phase of AD in adult TgF344-AD rats. These studies will provide foundational information regarding the interaction of AUD and AD and the findings will serve as a launch pad for future mechanistic studies.