The Contribution of Alcohol Abuse to the Development of Alzheimer's Pathology

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Abstract: The Contribution of Alcohol Abuse to the Development of Alzheimer?s Pathology This is a request for Alzheimer?s Disease (AD) Administrative Supplements for NIH grants (NOT-AG-18-008) to U01AA020023 (NADIA). Neuroimmune genes, e.g. genes expressing signaling molecules in brain first discovered as innate immune signals, are associated with neurodegeneration in alcohol use disorder and AD. We discovered adolescent intermittent ethanol exposure (AIE) causes persistent lasting increases in adult brain neuroimmune gene expression. AIE increased expression of brain proinflammatory cytokines, HMGB1, and Toll-like receptors (TLRs), and persistently increased markers of neurodegeneration in cortex and hippocampus. Further, AIE caused a persistent loss of adult forebrain ChAT+IR cholinergic neurons. HMGB1 is an immune signaling molecule in brain increased by stress, systemic immune activation and alcohol with increases persisting long after the initial stimulus as well as increasing with age into young adulthood. HMGB1 is increased in CSF of human AD patients, facilitates A? polymerization, and mediates neurite degeneration in an AD mouse model1. Each of these AIE findings is consistent with findings seen in humans with Alzheimer?s Disease (AD). Also, AD and AIE are associated with altered brain epigenetic gene regulation, synaptic proteins and dendrite morphology, cortical EEG, rsfMRI PFC-striatal connectivity as well adult disinhibition, anxiety, reward seeking, altered decision making and cognition. In humans, alcohol consumption peaks during adolescence and declines across the lifespan. Adolescent exposure to systemic endotoxin and/or AIE increase brain expression of neuroimmune signaling molecules that persist in brain for long periods. There are no studies on the impact of AIE on senescent neuroimmune induced neurodegeneration. AD onset is late in life, but may be related to earlier life insults. Few AD symptoms progress with age and are associated with neurodegeneration, and amyloid beta (A?42) and total Tau and phosphorylated Tau (p-tau). Chronic alcohol (5 weeks) increases amyloid precursor protein (APP) and beta secretase-1 (BACE1) in hippocampus and striatum2 and increases APP and BACE1 in vitro in neurons. A recently unified theory of AD etiology postulates that A? accumulation initiates an inflammatory cascade that induces hyper-excitability in cortical and hippocampal regions. Emerging evidence suggests AIE induces cortical hyper-excitability in adulthood, another commonality between AIE and AD. It is possible that adolescent binge drinking induces neuroimmune signaling that accelerates and/or increases AD neurodegeneration. The studies proposed in this supplement are needed to determine (1) if post-mortem alcoholic brain has AD markers (2) how AIE and binge ethanol in young adulthood alter AD markers later in life and (3) whether AD mouse models are more sensitive to AIE or binge ethanol during young adulthood. This supplement will test the overall hypothesis that AIE exposure, binge ethanol, and post-mortem human alcoholic brain show increases in AD-associated pathological and neuroimmune markers.