Probing Ethanol Induced Acceleration of Hindbrain and Amygdalar Pathology in an Alzheimer’s Disease Model

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Project Summary Alzheimer?s disease (AD) has a current economic impact of over $277 billion per year, and its prevalence is on the rise with more individuals dying from AD each year (up over 120% from 2000-2015). Recent studies have highlighted that stressful life experiences, including alcohol use disorder (AUD) may accelerate the progression of AD in the brain. Tangles of the microtubule binding protein tau forms the defining hallmark of all AD brains, and its pathological accumulation mediates AD progression. The earliest evidence of tau accumulation, decades prior to cognitive decline, occurs in a brain region that is highly engaged by stress: the pontine noradrenergic nucleus called the locus coeruleus (LC). Work in cell-based and animal models have demonstrated that 1) alcohol exposure may be linked to early tau pathogenesis and 2) pathological tau may originate in the LC and spread to synaptically connected brain regions including the bed nucleus of the stria terminalis (BNST) and the amygdala. Since withdrawal from alcohol is highly stressful, we hypothesize that intermittent exposure to high level alcohol will drive increased tau pathology in a mouse model of AD. This administrative supplement is in support of our U01 focused on examining how withdrawal from chronic intermittent ethanol (CIE) alters noradrenergic function within regions like the BNST and amygdala. Our preliminary data suggests that withdrawal from CIE bi-directionally regulates LC activity, with enhanced activation 6-8 hours in acute withdrawal, and suppression 24 hours in withdrawal. Repeated cycles of withdrawal from CIE may result in transiently high LC activation, spreading prion-like tauopathy, and further impinging LC physiology and behavior. Here we propose to test the impact of CIE in an AD setting. We will evaluate tau pathology, LC function, and AD-related learning and memory in three related but independent aims.