Significance of tau phosphorylation and protein kinase regulation in the pathogenesis of Alzheimer disease.
The role of the phosphatidylinositol-3 kinase pathway in the hyperphosphorylation of tau protein was investigated in cultured cells. Human kidney 293T-cells were cotransfected with tau and glycogen synthase kinase-3 (GSK-3) genes or tau and protein kinase B genes. The phosphorylation of tau protein was increased by cotransfection with GSK-3; however, it was decreased by cotransfection with protein kinase B. Human neuroblastoma SY5Y cells were treated with wortmannin, an inhibitor of phosphatidylinositol-3 kinase, and only transient (after 1 hour) activation of GSK-3 and hyperphosphorylation of tau protein were observed. However, continuous inactivation of protein kinase B was observed, suggesting the involvement of protein kinases other than 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, whereas treatment of cells with z-DEVD-fmk, an inhibitor of caspase-3, inhibited fragmentation of protein kinase C delta and induced continuous activation of GSK-3. It is suggested that fragmentation of protein kinase C delta during the process of apoptosis results in the phosphorylation and the inactivation of GSK-3. Those data suggest that, in Alzheimer disease, more complicated mechanisms are involved in the process of phosphorylation of tau protein predominantly regulated by P13K pathway.
Tanaka
T
T
Department of Clinical Neuroscience, Osaka University, Graduate School of Medicine, Suita, Japan.
Tsujio
I
I
Nishikawa
T
T
Shinosaki
K
K
Kudo
T
T
Takeda
M
M
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D017209:Apoptosis; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000378:metabolism*
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016875:tau Proteins; C497258:PRKCD protein, human