title: Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3.
abstract: Deposition of amyloid-beta protein (Abeta) is one of the most important pathologic features in Alzheimer's disease. It is well known that Abeta induces neuronal cell death through several pathogenic mechanisms. Although the role of glycogen synthase kinase (GSK)-3beta in the neurotoxicity of Abeta has been highlighted, there has been no report evaluating the effect of direct GSK-3beta inhibition on Abeta-induced neurotoxicity. Thus, in this study, the relationship between GSK-3beta activity and Abeta-induced neurotoxicity was explored. To investigate the role of GSK-3beta in Abeta-induced neurotoxicity, neurons were treated with amyloid beta-protein (1-42) (Abeta42) oligomers with or without the addition of a GSK-3beta inhibitor for 72 h. An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, and DAPI staining all showed that Abeta42 treatment alone resulted in decreased neuronal cell viability in a concentration-dependent manner. Abeta42 treatment significantly increased the activity of GSK-3beta and cell death signals such as phosphorylated Tau (pThr231), cytosolic cytochrome c, and activated caspase-3. Abeta42 treatment also resulted in decreased survival signals, including that of heat shock transcription factor-1. Treatment with a GSK-3beta inhibitor prevented Abeta-induced cell death. These results suggest that the neurotoxic effect of Abeta42 is mediated by GSK-3beta activation and that inhibition of GSK-3beta can reduce Abeta42-induced neurotoxicity.
authors.affiliation: Department of Neurology, College of Medicine, Hanyang University, Seongdong-Gu, Seoul, Republic of Korea.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Koh
authors.forename: Min Young
authors.initials: MY
authors.lastname: Noh
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004396:Coloring Agents; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D000076249:Heat Shock Transcription Factors; D007202:Indicators and Reagents; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013778:Tetrazolium Salts; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D004396:Coloring Agents; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D000076249:Heat Shock Transcription Factors; C000619709:Hsf1 protein, rat; D007202:Indicators and Reagents; D009498:Neurotoxins; D010446:Peptide Fragments; D013778:Tetrazolium Salts; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D045304:Cytochromes c; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3