Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo

Wendy Noble, Emmanuel Planel, Cindy Zehr, Vicki Olm, Jordana Meyerson, Farhana Suleman, Kate Gaynor, Lili Wang, John LaFrancois, Boris Feinstein, Mark Burns, Pavan Krishnamurthy, Yi Wen, Ratan Bhat, Jada Lewis, Dennis Dickson, Karen Duff

Research output: Contribution to journalArticlepeer-review

551 Scopus citations

Abstract

Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride- treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.

Original languageEnglish (US)
Pages (from-to)6990-6995
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number19
DOIs
StatePublished - May 10 2005

Keywords

  • Alzheimer's disease
  • Neurofibrillary tangles
  • Phosphorylation
  • Tau protein

ASJC Scopus subject areas

  • General

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