Significance of tau phosphorylation and protein kinase regulation in the pathogenesis of Alzheimer disease

The role of the phosphatidylinositol-3 kinase pathway in the hyperphosphory lation of tau protein was investigated in cultured cells. Human kidney 293T -cells were cotransfected with tau and glycogen synthase kinase-3 (GSK-3) g enes or tau and protein kinase B genes. The phosphorylation of tau protein was increased by cotransfection with GSK-3; however, it was decreased by co transfection with protein kinase B. Human neuroblastoma SY5Y cells were tre ated with wortmannin, an inhibitor of phosphatidylinositol-3 kinase, and on ly transient (after 1 hour) activation of GSK-3 and hyperphosphorylation of tau protein were observed. However, continuous inactivation of protein kin ase B was observed, suggesting the involvement of protein kinases other tha n protein kinase B in the phosphorylation and inactivation of GSK-3 after 3 hours. In cells treated with wortmannin, protein kinase C delta fragments were observed. and the protein kinase C activity increased after 3 hours, w hereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase-3, inhib ited fragmentation of protein kinase C delta and induced continuous activat ion of GSK-3. It is suggested that fragmentation of protein kinase C delta during the process of apoptosis results in the phosphorylation and the inac tivation of GSK-3. Those data suggest that, in Alzheimer disease, more comp licated mechanisms are involved in the process of phosphorylation of tau pr otein predominantly regulated by PI3K pathway.