Excessive alcohol use can cause structural and functional abnormalities of the brain and this has significant health, social and economic impact. Chronic alcohol abuse induces dementia which is associated with morphological, neurophysiological and biochemical changes in the central nervous system (CNS). The most devastating feature of brain damage following chronic alcohol abuse is neurodegeneration. The underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). Thiamine deficiency (TD) can damage the CNS. TD in humans may results from chronic alcohol exposure, genetic background, aging or nutritional status. The relationship between thiamine status and neuron susceptibility to alcohol- induced neurodegeneration, however, remains unclear. Autophagy is a lysosomal pathway involved in the turnover of cellular macromolecules and organelles. It provides the cells with an alternative source of intracellular building blocks and energy, thereby enhancing cell survival during nutrient deficiency or stress conditions. We hypothesize that TD may inhibit the autophagic pathways and impair this cellular self-protection mechanism. As a result, neurons are more susceptible to alcohol- induced neurodegeneration after chronic TD.
Three specific aims are proposed to test this hypothesis. We will first investigate whether the status of thiamine content determines neuron susceptibility to alcohol-induced neurodegeneration. We will next characterize the effect TD/alcohol on autophagy in the brain. Finally, we will determine the role of autophagy in alcohol/TD interaction and alcohol-induced neurodegeneration. As a unit, the proposal will elucidate the relationship between TD and neuron susceptibility to alcohol neurotoxicity and provide a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.
An estimated 7.5 percent of veterans are heavy drinkers and alcohol abuse is on the rise among combat veterans. Chronic alcohol abuse causes dementia and the most devastating feature of brain damage following chronic alcohol exposure is neurodegeneration. However, the underlying mechanisms remain unclear. Chronic alcohol consumption is often accompanied by the deficiency of thiamine (vitamin B1). This proposal will determine how thiamine deficiency (TD) and alcohol exposure interact and cause neurodegeneration in the central nervous system, providing a novel insight into the mechanisms underlying alcohol-induced neurodegeneration.