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Okadaic acid induces hyperphosphorylation of tau independently of mitogen-activated protein kinase activation.

Abstract
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.
AuthorsD T Ho, H Shayan, T H Murphy
JournalJournal of neurochemistry (J Neurochem) Vol. 68 Issue 1 Pg. 106-11 (Jan 1997) ISSN: 0022-3042 [Print] England
PMID8978715 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Flavonoids
  • tau Proteins
  • Okadaic Acid
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Tetradecanoylphorbol Acetate
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Topics
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
  • Cells, Cultured
  • Cerebral Cortex (cytology, metabolism)
  • Dose-Response Relationship, Drug
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (pharmacology)
  • Flavonoids (pharmacology)
  • Neuroglia (metabolism)
  • Neurons (metabolism)
  • Okadaic Acid (pharmacology)
  • Phosphorylation (drug effects)
  • Rats (embryology)
  • Tetradecanoylphorbol Acetate (pharmacology)
  • tau Proteins (metabolism)

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