Role of protein phosphatase-2A and-1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain

In Alzheimer disease brain the activities of protein phosphatase (PP)-2A and PP-1 are decreased and the microtubule-associated protein tau is abnormally hyperphosphorylated at several sites at serine/threonine, Employing rat forebrain slices kept metabolically active in oxygenated artificial CSF as a model system, we investigated the role of PP-2A/PP-1 in the regulation of some of the major abnormally hyperphosphorylated sites of tau and the protein kinases involved. Treatment of the brain slices with 1.0 muM okadaic acid inhibited similar to 65% of PP-ZA and produced hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422, No significant changes in the activities of glycogen synthase kinase-3 (GSK-3) and cyclin dependent protein kinases cdk5 and cdc2 were observed. Calyculin A (0.1 muM) inhibited similar to 50% PP-1, similar to 20% PP-2A, 50% GSK-3 and similar to 30% cdk5 but neither inhibited the activity of cyclin AMP dependent protein kinase A (PKA) nor resulted in the hyperphosphorylation of tau at any of the above sites. Treatment of brain slices with 1 muM okadaic acid plus 0.1 muM calyculin A inhibited similar to 100% Of both PP-2A and PP-1, similar to 80% of GSK-3, similar to 50% of cdk5 and similar to 30% of cdc2 but neither inhibited PKA nor resulted in the hyperphosphorylation of tau at any of the above sites. These studies suggest (i) that PP-1 upregulates the phosphorylation of tau at Ser 198/199/202 and Ser 396/404 indirectly by regulating the activities of GSK-3, cdk5 and cdc2 whereas PP-2A regulates the phosphorylation of tau directly by dephosphorylation at the above sites, and (ii) that a decrease in the PP-2A activity leads to abnormal hyperphosphorylation of tau at Ser 198/199/202, Ser 396/404 and Ser 422, (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.