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(American Journal of Pathology. 2003;163:845-858.)
© 2003 American Society for Investigative Pathology

Okadaic-Acid-Induced Inhibition of Protein Phosphatase 2A Produces Activation of Mitogen-Activated Protein Kinases ERK1/2, MEK1/2, and p70 S6, Similar to That in Alzheimer’s Disease

Jin-Jing Pei^*, Cheng-Xin Gong, Wen-Lin An^*, Bengt Winblad^*, Richard F. Cowburn^*, Inge Grundke-Iqbal and Khalid Iqbal

From the Division of Experimental Geriatrics,^* Karolinska Institutet, NEUROTEC, Huddinge, Sweden; and the Department of Neurochemistry, the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York

In Alzheimer’s disease (AD) brain the activity of protein phosphatase (PP)-2A is compromised and that of the extracellular signal-regulated protein kinase (ERK1/2) of the mitogen-activated protein kinase (MAPK) family, which can phosphorylate tau, is up-regulated. We investigated whether a decrease in PP-2A activity could underlie the activation of these kinases and the abnormal hyperphosphorylation of tau. Rat brain slices, 400-µm-thick, kept under metabolically active conditions in oxygenated (95% O₂, 5% CO₂) artificial CSF were treated with 1.0 µmol/L okadaic acid (OA) for 1 hour at 33°C. Under this condition, PP-2A activity was decreased to 35% of the vehicle-treated control slices, and activities of PP-1 and PP-2B were not affected. In the OA-treated slices, we observed a dramatic increase in the phosphorylation/activation of ERK1/2, MEK1/2, and p70 S6 kinase both immunohistochemically and by Western blots using phosphorylation-dependent antibodies against these kinases. Treatment of 6-µm sections of the OA-treated slices with purified PP-2A reversed the phosphorylation/activation of these kinases. Hyperphosphorylation of tau at several abnormal hyperphosphorylation sites was also observed, as seen in AD brain. These results suggest 1) that PP-2A down-regulates ERK1/2, MEK1/2, and p70 S6 kinase activities through dephosphorylation at the serine/threonine residues of these kinases, and 2) that in AD brain the decrease in PP-2A activity could have caused the activation of ERK1/2, MEK1/2, and p70 S6 kinase, and the abnormal hyperphosphorylation of tau both via an increase in its phosphorylation and a decrease in its dephosphorylation.

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