| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print September 20, 2004
Pathophysiology Department,Neuroscience Institute,Tongji Medical College, Hua-Zhong University of Science and Technology, Wuhan 430030 P.R.China
Corresponding Author: wangjz{at}mails.tjmu.edu.cn
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 is prephosphorylated by PKA in rat brain
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Liu, Z. Liang, J. Wegiel, Y.-W. Hwang, K. Iqbal, I. Grundke-Iqbal, N. Ramakrishna, and C.-X. Gong Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome FASEB J, September 1, 2008; 22(9): 3224 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Liang, T. Dunckley, T. G. Beach, A. Grover, D. Mastroeni, K. Ramsey, R. J. Caselli, W. A. Kukull, D. McKeel, J. C. Morris, et al. Altered neuronal gene expression in brain regions differentially affected by Alzheimer's disease: a reference data set Physiol Genomics, April 21, 2008; 33(2): 240 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chen, B. Li, I. Grundke-Iqbal, and K. Iqbal I PP2A 1 Affects Tau Phosphorylation via Association with the Catalytic Subunit of Protein Phosphatase 2A J. Biol. Chem., April 18, 2008; 283(16): 10513 - 10521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-Q. Zhu, S.-H. Wang, D. Liu, Y.-Y. Yin, Q. Tian, X.-C. Wang, Q. Wang, J.-G. Chen, and J.-Z. Wang Activation of Glycogen Synthase Kinase-3 Inhibits Long-Term Potentiation with Synapse-Associated Impairments J. Neurosci., November 7, 2007; 27(45): 12211 - 12220. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-L. Li, H.-H. Wang, S.-J. Liu, Y.-Q. Deng, Y.-J. Zhang, Q. Tian, X.-C. Wang, X.-Q. Chen, Y. Yang, J.-Y. Zhang, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer's neurodegeneration PNAS, February 27, 2007; 104(9): 3591 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Plattner, M. Angelo, and K. P. Giese The Roles of Cyclin-dependent Kinase 5 and Glycogen Synthase Kinase 3 in Tau Hyperphosphorylation J. Biol. Chem., September 1, 2006; 281(35): 25457 - 25465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Zhang, Y.-F. Xu, Y.-H. Liu, J. Yin, H.-L. Li, Q. Wang, and J.-Z. Wang Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms FASEB J, July 1, 2006; 20(9): 1431 - 1442. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
