GSK-3beta and oxidative stress in aged brain. Role of poly(ADP- -ribose) polymerase-1

Glycogen synthase kinase-3 (GSK-3) plays important roles in the regulation of glycogen and protein synthesis. In Alzheimer's disease it is responsible for hyperphosphorylation of tau. However, the role of GSK-3beta in brain aging and in neurodegenerative diseases is not fully elucidated. Our aim was to determine the protein level of GSK-3beta and its active, tyrosine 216-phosphorylated form in adult and aged brain parts. Moreover, lipid and protein oxidation and nuclear NF-kappaB translocation were measured and correlated with the activity of PARP-1, the nuclear target for free radical signalling. The GSK-3beta/PARP-1 relationship was investigated. Adult (4 months) and old (24 months) rats were used. PARP-1 inhibitor 3-aminobenzamide (3-AB) was injected subcutaneously for 5 days in a dose of 10 and 30 mg/kg b.w. On the 8th day object recognition test and open field test were performed.Biochemical,radiochemical,immunochemical and spectrophotometric methods were applied. Our data indicated similar protein level and activity of GSK-3beta in aged and adult brain cortex, hippocampus, striatum and cerebellum. A significantly higher level of p65NF-kappaB subunit was found in the nuclei of aged hippocampus. Moreover, our previous study presented higher PARP-1 activity in aged hippocampus and brain cortex versus adult. These results indicated an enhancement of oxidative stress and altered susceptibility of macromolecules to oxidative stress in aged brain. Subsequently it was found that 3-AB significantlychangedthelevelofactiveformofGSK-3beta(Tyr216) in the hippocampus and brain cortex and at high dose decreased the locomotor activity of aged rats. These results indicated that PARP-1 may play an important role in the regulation of GSK-3beta. Under massive oxidative stress PARP inhibitor(s) may protect the brain against both excessive poly(ADP-ribosy)lation and GSK-3beta activation.