title: Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans.
abstract: Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration.
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea; Department of Anatomy and Cell Biology, Gachon University Graduate school of Medicine, Incheon, Korea.
authors.forename: Kyunghee
authors.initials: K
authors.lastname: Byun
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Delger
authors.initials: D
authors.lastname: Bayarsaikhan
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Bayarsaikhan
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Myeongjoo
authors.initials: M
authors.lastname: Son
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Seyeon
authors.initials: S
authors.lastname: Oh
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea.
authors.forename: Jaesuk
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Bioengineering, University of California, Berkeley, CA, United States of America.
authors.forename: Hye-In
authors.initials: HI
authors.lastname: Son
authors.affiliation: Department of Anatomy and Neurobiology, and Institute of Neurodegeneration and Neuroregeneration, College of Medicine, Kangwon National University, Chuncheon, Korea.
authors.forename: Moo-Ho
authors.initials: MH
authors.lastname: Won
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
authors.affiliation: Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Korea; Department of Anatomy and Cell Biology, Gachon University Graduate school of Medicine, Incheon, Korea.
authors.forename: Bonghee
authors.initials: B
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000418:Albumins / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol; D006801:Humans; D008297:Male; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats
chemical_list: D000418:Albumins; D000431:Ethanol