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 microM okadaic acid inhibited approximately 65% of PP-2A 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 microM) inhibited approximately 50% PP-1, approximately 20% PP-2A, 50% GSK-3 and approximately 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 microM okadaic acid plus 0.1 microM calyculin A inhibited approximately 100% of both PP-2A and PP-1, approximately 80% of GSK-3, approximately 50% of cdk5 and approximately 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.
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Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.
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D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D008387:Marine Toxins; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D016548:Prosencephalon / Q000201:enzymology; D054648:Protein Phosphatase 2; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D016875:tau Proteins; D019319:Okadaic Acid; C059041:calyculin A; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2