Songin Martyna, Jeśko Henryk, Czapski Grzegorz, Adamczyk Agata, Strosznajder Robert P
Department of Cellular Signalling, Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., PL-02106 Warsaw, Poland.
Folia Neuropathol. 2007;45(4):220-9.
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.
糖原合酶激酶-3（GSK-3）在糖原和蛋白质合成的调节中发挥着重要作用。在阿尔茨海默病中，它负责tau蛋白的过度磷酸化。然而，GSK-3β在脑老化和神经退行性疾病中的作用尚未完全阐明。我们的目的是确定成年和老年脑区中GSK-3β及其活性的酪氨酸216磷酸化形式的蛋白水平。此外，还测量了脂质和蛋白质氧化以及核NF-κB易位，并将其与自由基信号的核靶点PARP-1的活性相关联。研究了GSK-3β/PARP-1的关系。使用成年（4个月）和老年（24个月）大鼠。以10和30mg/kg体重的剂量皮下注射PARP-1抑制剂3-氨基苯甲酰胺（3-AB），持续5天。在第8天进行物体识别测试和旷场试验。应用了生化、放射化学、免疫化学和分光光度法。我们的数据表明，老年和成年脑皮质、海马、纹状体和小脑中GSK-3β的蛋白水平和活性相似。在老年海马体的细胞核中发现p65NF-κB亚基的水平显著更高。此外，我们之前的研究表明，与成年相比，老年海马体和脑皮质中的PARP-1活性更高。这些结果表明老年脑中氧化应激增强，大分子对氧化应激的敏感性改变。随后发现，3-AB显著改变了海马体和脑皮质中GSK-3β（Tyr216）活性形式的水平，高剂量时降低了老年大鼠的运动活性。这些结果表明PARP-1可能在GSK-3β的调节中起重要作用。在大量氧化应激下，PARP抑制剂可能保护大脑免受过度的多聚（ADP-核糖基）化和GSK-3β激活。
