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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001721-06
Application #
9832131
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2013-10-01
Project End
2022-12-31
Budget Start
2020-01-01
Budget End
2020-12-31
Support Year
6
Fiscal Year
2020
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
Luo, Jia (2015) Effects of Ethanol on the Cerebellum: Advances and Prospects. Cerebellum 14:383-5
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

Showing the most recent 10 out of 13 publications