Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3*
- From the ‡Department of Pharmacology, the Center for Neurodegenerative Disease Research, the Department of Pathology and Laboratory Medicine, and the §Howard Hughes Medical Institute and Department of Medicine (Hematology-Oncology) and Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Abstract
Lithium is one of the most widely used drugs for treating bipolar (manic-depressive) disorder. Despite its efficacy, the molecular mechanism underlying its action has not been elucidated. One recent study has proposed that lithium inhibits glycogen synthase kinase-3 and thereby affects multiple cellular functions. Because glycogen synthase kinase-3 regulates the phosphorylation of tau (microtubule-binding protein that forms paired helical filaments in neurons of the Alzheimer’s disease brain), we hypothesized that lithium could affect tau phosphorylation by inhibiting glycogen synthase kinase-3. Using cultured human NT2N neurons, we demonstrate that lithium reduces the phosphorylation of tau, enhances the binding of tau to microtubules, and promotes microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3. These results provide new insights into how lithium mediates its effects in the central nervous system, and these findings could be exploited to develop a novel intervention for Alzheimer’s disease.
Footnotes
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↵* This work was supported by grants from the NIA, National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ To whom correspondence should be addressed: Center for Neurodegenerative Disease Research, Dept. of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, HUP/Maloney 3, 3600 Spruce St., Philadelphia, PA 19104. Tel.: 215-662-6427; Fax: 215-349-5909; E-mail: vmylee{at}mail.med.upenn.edu.
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↵1 The abbreviations used are: GSK-3, glycogen synthase kinase-3; SFV, Semliki Forest virus; WT, wild type; DMEM-HG, Dulbecco’s modified Eagle’s medium with high glucose; Mes, 4-morpholineethanesulfonic acid; PAGE, polyacrylamide gel electrophoresis; Pipes, 1,4-piperazinediethanesulfonic acid; MAb, monoclonal antibody.
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↵2 M. Hong, unpublished data.
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- Received May 29, 1997.
- Revision received July 14, 1997.
