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

  1. Wendy Noble * , †,
  2. Emmanuel Planel * , †,
  3. Cindy Zehr ‡,
  4. Vicki Olm *,
  5. Jordana Meyerson *,
  6. Farhana Suleman *,
  7. Kate Gaynor *,
  8. Lili Wang *,
  9. John LaFrancois *,
  10. Boris Feinstein *,
  11. Mark Burns *,
  12. Pavan Krishnamurthy *,
  13. Yi Wen *,
  14. Ratan Bhat §,
  15. Jada Lewis ‡,
  16. Dennis Dickson ‡, and
  17. Karen Duff * ,
  1. *Center for Dementia Research, Nathan S. Kline Institute, New York University, 140 Old Orangeburg Road, Orangeburg, NY 10962; ‡Department of Neuroscience, Mayo Clinic, 5400 San Pablo Road, Jacksonville, FL 32224; and §AstraZeneca R&D, 15185 Södertalje, Sweden

  1. Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved March 21, 2005 (received for review January 19, 2005)

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.

Footnotes

  • ↵ To whom correspondence should be addressed. E-mail: duff{at}nki.rfmh.org.

  • ↵ † W.N. and E.P. contributed equally to this work.

  • This paper was submitted directly (Track II) to the PNAS office.

  • Abbreviations: Aβ, β-amyloid; AD, Alzheimer's disease; GSK-3, glycogen synthase kinase-3; LFB, Luxol fast blue; NFT, neurofibrillary tangle.

  • Freely available online through the PNAS open access option.

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