Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthast kinase-3

Abstract

Deposition of amyloid-beta protein (A beta) is one of the most important pathologic features in Alzheimer's disease. it is well known that A beta induces neuronal cell death through several pathogenic mechanisms. Although the role of glycogen synthase kinase (GSK)-3 beta in the neurotoxicity of A beta has been highlighted, there has been no report evaluating the effect of direct GSK-3 beta inhibition on A beta-induced neurotoxicity. Thus, in this study, the relationship between GSK-3 beta activity and A beta-induced neurotoxicity was explored. To investigate the role of GSK-3 beta in A beta-induced neurotoxicity, neurons were treated with amyloid betaprotein (1-42) (A beta 42) oligomers with or without the addition of a GSK-3 beta inhibitor for 72 h. An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, and DAPT staining all showed that A beta 42 treatment alone resulted in decreased neuronal cell viability in a concentration- dependent manner. A beta 42 treatment significantly increased the activity of GSK-3 beta and cell death signals such as phosphorylated Tau (pThr231), cytosolic cytochrome c, and activated caspase-3. A beta 42 treatment also resulted in decreased survival signals, including that of heat shock transcription factor-1. Treatment with a GSK-3 beta inhibitor prevented A -induced cell death. These results suggest that the neurotoxic effect of A beta 42 is mediated by GSK-3 beta activation and that inhibition of GSK-3 beta can reduce A beta 42-induced neurotoxicity.