Okadaic acid induces hyperphosphorylation of tau independently of mitogen-activated protein kinase activation.
Hyperphosphorylation of the microtubule-associated protein tau is a characteristic of Alzheimer brain tissue. Recent in vitro data suggest that mitogen-activated protein kinase (MAPK), a proline-directed protein kinase, phosphorylates the sites on tau common to Alzheimer's disease. Using an okadaic acid-induced tau hyperphosphorylation model, we have tested the requirement for MAPK activity, using a specific inhibitor ¿PD098059 [2-(2'-amino-3'-methoxyphenyl)oxanaphthalen-4-one]¿ of the MAPK activator Mek1. Mobility shift, phosphoepitope analysis, and direct measurement of kinase activity indicated that the Mek1 inhibitor dose-dependently blocked basal and okadaic acid-induced MAPK activation. Despite a block of MAPK activation by this inhibitor, robust tau hyperphosphorylation was observed in response to okadaic acid. In addition, activation of MAPK by phorbol 12-myristate 13-acetate did not result in tau phosphorylation, indicating that in primary cultures of cortical neurons elevated MAPK activity is not sufficient to induce tau hyperphosphorylation.
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Kinsmen Laboratory, Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Shayan
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Murphy
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D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats / Q000196:embryology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D016875:tau Proteins; D019319:Okadaic Acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one