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J. Biol. Chem., Vol. 279, Issue 48, 50078-50088, November 26, 2004

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Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain^*

Shi Jie Liu, Jia Yu Zhang, Hong Lian Li, Zheng Yu Fang, Qun Wang, Heng Mei Deng, Cheng Xin Gong¶, Inge Grundke-Iqbal¶, Khalid Iqbal¶**, and Jian Zhi Wang||

From the Pathophysiology Department, Neuroscience Institute, Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430030, People's Republic of China and the ^¶Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314

Microtubule-associated protein tau is abnormally hyperphosphorylated in Alzheimer's 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 A (PKA) activator, into the lateral ventricle of brain in adult rats induced activation of PKA by severalfold and concurrently enhanced the phosphorylation of tau at Ser-214, Ser-198, Ser-199, and or Ser-202 (Tau-1 site) and Ser-396 and or Ser-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 the phosphorylation at both the Tau-1 and the PHF-1 sites is induced 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 MAPK 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 R_p-adenosine 3',5'-cyclic monophosphorothioate triethyl ammonium salt, 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 and the PHF-1 sites 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.

Received for publication, June 2, 2004 , and in revised form, September 14, 2004.

^* This work was supported by grants from the National Natural Science Foundation of China (Grants 39925012, 30170221, and 30100213), Science and Technology Committee of China (Grant G1999054007), National Educational Committee of China (Grant 2001-171), the Li Foundation, Inc., USA, and National Institutes of Health Grant AG19158. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^|| To whom correspondence may be addressed: Pathophysiology Department, Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430030. Tel.: 086-27-8369-2625; Fax: 086-27-8369-3883; E-mail: wangjz{at}mails.tjmu.edu.cn. ** To whom correspondence may be addressed: Dept. of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Rd., Staten Island, NY 10314-6399. Tel.: 718-494-5259; Fax: 718-494-1080; E-mail: iqbalk{at}worldnet.att.net.

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