OKADAIC ACID ENHANCES ABNORMAL PHOSPHORYLATION ON TAU PROTEINS

Tau proteins are one of the microtubule-associated proteins (MAPs) and show promoting activity on microtubule assembly. Tau proves to be the major constituent of Alzheimer's paired helical filaments, in which t au is found to be different from normal tau in that it is abnormally p hosphorylated. To examine the effect of the abnormal phosphorylation o n microtubule assembly, we obtained abnormally phosphorylated tau that was made in vitro by hyperphosphorylation with ATP or with ATP and ok adaic acid, a drug inhibiting phosphatase, mainly 1 and 2A. We confirm ed the biochemical properties of abnormally phosphorylated tau based o n its retarded gel mobility and immunoreactivity to anti-PHF. We found that abnormally phosphorylated tau was able to promote the polymeriza tion of microtubules but showed less activity as compared with normall y phosphorylated tau. This effect of ATP on abnormal phosphorylation o f tau was enhanced when okadaic acid was added in the phosphorylation reaction mixture during microtubule assembly. It is of significance th at phosphatase activity as well as kinase activity are involved in the formation of abnormal tau. The present evidence suggests the simultan eous occurrence of microtubule disassembly and the pathogenesis of pai red helical filaments following the abnormal phosphorylation of tau.