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Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations
S Lovestone1, D R Davis, M T Webster
1Department of Psychiatry, Institute of Psychiatry, London, United Kingdom.
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.
Insights
Lithium treatment reversibly reduces tau phosphorylation by inhibiting glycogen synthase kinase-3 (GSK-3). This action influences tau
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- The precise mechanism of lithium's action in the brain is not fully understood.
- Emerging evidence suggests lithium may inhibit glycogen synthase kinase-3 (GSK-3).
- GSK-3 phosphorylates tau protein, which is crucial for stabilizing neuronal microtubules.
Purpose of the Study:
- To investigate the effect of lithium on tau phosphorylation in neuronal and non-neuronal cells.
- To examine the role of GSK-3 in lithium-induced changes in tau phosphorylation.
Main Methods:
- Neurons and transfected cells were treated with lithium.
- Tau phosphorylation was analyzed using western blotting and immunocytochemistry.
- Green fluorescent protein (GFP)-tagged tau was used to visualize its behavior in living cells.
Main Results:
- Lithium administration reversibly decreased tau phosphorylation at therapeutic concentrations.
- Phosphorylated tau, when influenced by GSK-3, associated with microtubules and formed bundles upon lithium treatment.
- Removal of lithium led to the dissociation of tau from microtubules and bundle dissolution in living cells.
Conclusions:
- Lithium exhibits multiple effects in the brain, including the inhibition of GSK-3-mediated tau phosphorylation.
- These findings provide insights into the molecular mechanisms of mood-stabilizing drugs.
- The study has implications for understanding the molecular basis of affective disorders.