Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK-1/2, and p70 S6, similar to that in Alzheimer's disease

In Alzheimer's disease (AD) brain the activity of protein phosphatase (PP)-2A is compromised and that of the extracellular signal-regulated protein kinase (Ell 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-mum-thick, kept under metabolically active conditions in oxygenated (95% O-2, 5% CO2) artificial CSF were treated with 1.0 mumol/L okadaic acid (OA) for I hour at 33degreesC. Under this condition, PP-2A activity was decreased to similar to35% 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 Ell MEK1/2, and p70 S6 kinase both immunohistochemically and by Western blots using phosphorylation-dependent antibodies against these kinases. Treatment of 6-mum sections of the OA-treated slices with purified PP-2A reversed the phosphorylation/activation of these kinases. Hyper-phosphorylation 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.