Alcohol abuse causes many long-lasting health consequences; one of which is impaired cognitive functioning known as alcohol-associated dementia (AAD). AAD is caused by the morphological, neurophysiological and biochemical changes in the brain. The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. Alcohol abuse is frequently associated with the deficiency of thiamine (vitamin B1). Besides alcohol exposure, other factors, such as genetic background, aging or nutritional status also contribute to thiamine deficiency (TD). The relationship between TD and alcohol-induced neurodegeneration remains unclear. Our studies indicate that TD exacerbated alcohol-induced neurodegeneration. Alcohol exposure caused significant endoplasmic reticulum ER stress in the brain. We hypothesize that TD causes a deficiency in unfolded protein response (UPR) which function as a protective response to alleviate ER stress-induced damage. MANF is an evolutionarily conserved neurotrophic factor and an important UPR component. We further hypothesize that MANF is a key protein that maintains ER homeostasis and TD-induced deficiency in MANF makes neurons more susceptible to alcohol-induced ER stress and neurodegeneration. In this proposal, we will first investigate the effect of TD on MANF expression. We will then determine the role of MANF in alcohol-induced ER stress and neurodegeneration. Finally, we will determine whether manipulation of MANF expression in the brain can alter TD/alcohol-induced behavioral deficits. As a unit, the proposal will investigate the mechanisms of how TD exacerbates alcohol-induced neurodegeneration and establish a protective role of MANF in alcohol-induced neurodegeneration. It will not only provide a novel insight into the interaction between TD and alcohol exposure in the context of AAD but also identify potential therapeutic targets for the treatment of AAD.

Alcohol abuse is a serious health problem among veterans. Chronic alcohol abuse causes brain damage and thiamine (vitamin B1) deficiency (TD). This proposal will investigate how TD and alcohol exposure interact to induce neurodegeneration in the central nervous system. We will also identify neurotrophic factors that can offer protection and explore potential neuroprotective strategy to ameliorate alcohol-induced brain damage.