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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001721-03
Application #
8966631
Study Section
Neurobiology A (NURA)
Project Start
2013-10-01
Project End
2017-09-30
Budget Start
2015-10-01
Budget End
2016-09-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
VA Medical Center - Lexington, KY
Department
Type
DUNS #
018766373
City
Lexington
State
KY
Country
United States
Zip Code
40502
Wang, Yongchao; Wang, Xin; Li, Hui et al. (2018) Binge ethanol exposure induces endoplasmic reticulum stress in the brain of adult mice. Toxicol Appl Pharmacol 356:172-181
Zhang, Kai; Wang, Haiping; Xu, Mei et al. (2018) Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain. J Neuroinflammation 15:197
Wang, Xin; Zhang, Kai; Yang, Fanmuyi et al. (2018) Minocycline protects developing brain against ethanol-induced damage. Neuropharmacology 129:84-99
Wang, Xin; Xu, Mei; Frank, Jacqueline A et al. (2017) Thiamine deficiency induces endoplasmic reticulum stress and oxidative stress in human neurons derived from induced pluripotent stem cells. Toxicol Appl Pharmacol 320:26-31
Liu, Dexiang; Ke, Zunji; Luo, Jia (2017) Thiamine Deficiency and Neurodegeneration: the Interplay Among Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy. Mol Neurobiol 54:5440-5448
Ren, Zhenhua; Wang, Xin; Xu, Mei et al. (2016) Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas. Oncotarget 7:54303-54316
Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin et al. (2016) Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation. Toxicol Appl Pharmacol 308:11-19
Wang, Haiping; Wang, Xin; Ke, Zun-Ji et al. (2015) Tunicamycin-induced unfolded protein response in the developing mouse brain. Toxicol Appl Pharmacol 283:157-67
Yang, Fanmuyi; Luo, Jia (2015) Endoplasmic Reticulum Stress and Ethanol Neurotoxicity. Biomolecules 5:2538-53
Luo, Jia (2015) Effects of Ethanol on the Cerebellum: Advances and Prospects. Cerebellum 14:383-5

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