engleski

Expression of glycogen synthase kinase-3 (GSK-3)and protein kinase B (Act/PKB) in hippocampus of rats with experimental Alzheimer's disease

Objectives. The objective of the study was to investigate the expression of enzymes in insulin signalling cascade, protein kinase B (Act/PKB) and downstream glycogen synthase kinase-3 (GSK-3), in the hippocampus of rats with experimental Alzheimer's disease (streptozotocin /STZ/ intracerebroventricularly /icv/ treated rats). Material and Methods. GSK-3 and Act/PKB were measured by Western blot analysis, one month after the icv administration of STZ (1 mg/kg), as well as after the icv administration of glucose transporter 2 (GLUT2) inhibitor 5-thio-D-glucose (TG ; 150 &#956; g/kg), and their combination (TG+STZ). Cognitive functions were tested by Morris Water Maze Test. Statistical significance was analysed by Kruskal-Wallis ANOVA median test and Mann-Whitney U test, p<0.05. Results. In the STZ group only the expression of phosphorylated GSK form (pGSK) was significantly increased. Treatment with TG alone significantly increased the expression of pGSK and Act/PKB. Combined TG+STZ treatment tended to reduce the STZ- and TG-induced increase in pGSK expression (p=0.067 and 0.075 by Mann-Whitney U test), while Act/PKB expression remained significantly increased in comparison to the control group. Nonphosphorylated GSK was unchanged after all the treatments. Significant deficits in learning and memory were found in all treatments in comparison to the control group. Conclusions. Our results demonstrate increased hippocampal pGSK levels in one month lasting experimental Alzheimer's disease, supporting the hypothesis of altered brain insulin signalling in this disorder. Unchanged Act/PKB and GSK protein level may point to the disturbances at the level of other insulin-dependent regulators of GSK phoshorylation status. This effect, as well as cognitive deficits could not be blocked by combined treatment of STZ and GLUT2 inhibitor, which prevents peripheral STZ toxicity. Blockade of GLUT2 itself seems to affect brain insulin, as demonstrated at the level of insulin signalling and cognitive behaviour. Supported by DAAD (Germany) and the Croatian Ministry of Science, Technology and Sport (0108253).

Streptozotocin; protein kinase B; glycogen syntase kinase-3; hippocampus

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