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 an d PP-1 are decreased and the microtubule-associated protein tau is abnormal ly 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 prot ein kinases involved. Treatment of the brain slices with 1.0 muM okadaic ac id inhibited similar to 65% of PP-ZA and produced hyperphosphorylation of t au at Ser 198/199/202, Ser 396/404 and Ser 422, No significant changes in t he activities of glycogen synthase kinase-3 (GSK-3) and cyclin dependent pr otein 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% cdk 5 but neither inhibited the activity of cyclin AMP dependent protein kinase A (PKA) nor resulted in the hyperphosphorylation of tau at any of the abov e sites. Treatment of brain slices with 1 muM okadaic acid plus 0.1 muM cal yculin A inhibited similar to 100% Of both PP-2A and PP-1, similar to 80% o f GSK-3, similar to 50% of cdk5 and similar to 30% of cdc2 but neither inhi bited PKA nor resulted in the hyperphosphorylation of tau at any of the abo ve sites. These studies suggest (i) that PP-1 upregulates the phosphorylati on of tau at Ser 198/199/202 and Ser 396/404 indirectly by regulating the a ctivities of GSK-3, cdk5 and cdc2 whereas PP-2A regulates the phosphorylati on of tau directly by dephosphorylation at the above sites, and (ii) that a decrease in the PP-2A activity leads to abnormal hyperphosphorylation of t au at Ser 198/199/202, Ser 396/404 and Ser 422, (C) 2000 Federation of Euro pean Biochemical Societies. Published by Elsevier Science B.V. All rights r eserved.