OKADAIC ACID INDUCES HYPERPHOSPHORYLATION OF TAU INDEPENDENTLY OF MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION

Hyperphosphorylation of the microtubule-associated protein tau is a ch aracteristic of Alzheimer brain tissue. Recent in vitro data suggest t hat mitogen-activated protein kinase (MAPK), a proline-directed protei n kinase, phosphorylates the sites on tau common to Alzheimer's diseas e. Using an okadaic acid-induced tau hyperphosphorylation model, we ha ve tested the requirement for MAPK activity, using a specific inhibito r {PD098059 2-(2'-amino-3'-methoxyphenyl)oxanaphthalen-4-one]} of the MARK activator Mek1. Mobility shift, phosphoepitope analysis, and dire ct measurement of kinase activity indicated that the Mek1 inhibitor do se-dependently blocked basal and okadaic acid-induced MAPK activation. Despite a block of MARK activation by this inhibitor, robust tau hype rphosphorylation was observed in response to okadaic acid. In addition , activation of MARK by phorbol 12-myristate 13-acetate did not result in tau phosphorylation, indicating that in primary cultures of cortic al neurons elevated MAPK activity is not sufficient to induce tau hype rphosphorylation.