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Papers In Press, published online ahead of print September 15, 2004
Department of Neurochemistry, NYS Institute for Basic Research, Staten Island, NY 10314-6399
Corresponding Author: iqbalk{at}worldnet.att.net
Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer disease (AD) and other tauopathies and is believed to lead to neurodegeneration in this family of diseases. Here we show that infusion of forskolin, a specific cAMP-dependent protein kinase (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by several fold and concurrently enhanced the phosphorylation of tau at Ser-214; Ser-198, -199, and or -202 (Tau-1 site); and Ser-396 and or -404 (PHF-1 site), which are among the major abnormally hyperphosphorylated sites seen in AD. PKA activation positively correlated to the extent of tau phosphorylation at these sites. Infusion of forskolin together with PKA inhibitor or glycogen synthase kinase-3 (GSK-3) inhibitor revealed that the phosphorylation of tau at Ser-214 was catalyzed by PKA, and that at the Tau-1 site and the PHF-1 site by basal level of GSK-3 because forskolin activated PKA and not GSK-3 and inhibition of the latter inhibited the phosphorylation at Tau-1 and PHF-1 sites. Inhibition of cdc2, cdk5 or MAP kinase had no significant effect on the forskolin-induced hyperphosphorylation of tau. Forskolin inhibited spatial memory in a dose-dependent manner in the absence but not in the presence of Rp-cAMPs, a PKA inhibitor. These results demonstrate for the first time that phosphorylation of tau by PKA primes it for phosphorylation by GSK-3 at the Tau-1 site and the PHF-1 site and that an associated loss in spatial memory is inhibited by inhibition of the hyperphosphorylation of tau. These data provide a novel mechanism of the hyperphosphorylation of tau and identify both PKA and GSK-3 as promising therapeutic targets for AD and other tauopathies.
J. Biol. Chem, 10.1074/jbc.M406109200
Submitted on June 2, 2004
Revised on September 14, 2004
Accepted on September 15, 2004
Tau becomes a more favorable substrate for GSK-3 when it Ii prephosphorylated by PKA in rat brain
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