Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356

The regulation of the activity of CaMKII by PP-1 and PP-2A, as well as the role of this protein kinase in the phosphorylation of tau protein in forebrain were investigated. The treatment of metabolically active rat brain slices with 1.0 muM okadaic acid (OA) inhibited similar to 65% of PP-2A and had no significant effect on PP-1 in the 16 000 X g tissue extract. Calyculin A (CL-A), 0.1 muM under the same conditions, inhibited similar to 50% of PP-1 and similar to 20% of PP-2A activities. In contrast, a mixture of OA and CL-A practically completely inhibited both PP-2A and PP-1 activities. The inhibition of the two phosphatase activities or PP-2A alone resulted in an similar to2-fold increase in CaMKII activity and an similar to8-fold increase in the phosphorylation of tau at Ser 262/356 in 60 min. Treatment of the brain slices with KN-62, an inhibitor of the autophosphorylation of CaMKII at Thr 286/287, produced similar to 60% inhibition in CaMKII activity and no significant effect on tau phosphorylation at Ser 262/356, The KN-62-treated brain slices when further treated with OA and CL-A did not show any change in CaMKII activity. In vitro, both PP-2A and PP-1 dephosphorylated tau at Ser 262/356 that was phosphorylated with purified CaMKII. These studies suggest (i) that in mammalian forebrain the cytosolic CaMKII activity is regulated mainly by PP-2A, (ii) that CaMKII is the major tau Ser 262/356 kinase in brain, and (iii) that a decrease in PP-2A/PP-1 activities in the brain leads to hyperphosphorylation of tau not only bg inhibition of its dephosphorylation but also by promoting the CaMKII activity. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.