Lithium reduces tau phosphorylation: Effects in living cells and in neurons at therapeutic concentrations

Simon Lovestone, Danny R. Davis, Marie Therese Webster, Stefanie Kaech, Jean Pierre Brion, Andrew Matus, Brian H. Anderton

Research output: Contribution to journalArticle

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Abstract

Background: The mechanism of action of lithium remains to be determined satisfactorily. Recent studies suggested a possible role in inhibiting glycogen synthase kinase-3 (GSK-3), previously shown to phosphorylate the protein tau. Tau is expressed mainly in neurons, where it functions to stabilize microtubules in a phosphorylation-dependent manner. Methods: Neurons and transfected non-neuronal cells were treated with lithium and the phosphorylation of tau at multiple epitopes examined by western blotting and by immunocytochemistry. Using green fluorescent protein as a tag we examined the effects of lithium on phosphorylated tau in living cells. Results: Lithium reversibly reduced tau phosphorylation at therapeutic concentrations, and even at high concentrations did not alter neuronal morphology. Green fluorescent protein tagged-tau when phosphorylated by GSK-3 was diffusely distributed; treatment with lithium resulted in association with microtubules and then bundle formation. Removing lithium allowed observation of the dissolution of bundles and gradual dissociation of tau from microtubules in living cells. Conclusions: Lithium may have multiple effects in brain, but at least one action is demonstrated to be a relative inhibition of GSK-3- induced tau phosphorylation. These results carry implications for future studies of the actions of mood-stabilizing drugs and indeed of the molecular mechanisms of affective disorders.

Original languageEnglish (US)
Pages (from-to)995-1003
Number of pages9
JournalBiological Psychiatry
Volume45
Issue number8
DOIs
StatePublished - Apr 15 1999

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Keywords

  • Glycogen synthase kinase- 3
  • Lithium
  • Microtubules
  • Neuron
  • Phosphorylation
  • Tau

ASJC Scopus subject areas

  • Biological Psychiatry

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