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

Background: The mechanism of action of lithium remains to be determined sat isfactorily, Recent studies suggested a possible role in inhibiting glycoge n synthase kinase-3 (GSK-3), previously shown to phosphorylate the protein tau. Tau is expressed mainly in neurons, where it functions to stabilize mi crotubules in a phosphorylation-dependent manner, Methods: Neurons and transfected non-neuronal cells were treated with lithi um and the phosphorylation of tau at multiple epitopes examined by western blotting and by immunocytochemistry. Using green fluorescent protein as a t ag we examined the effects of lithium on phosphorylated tau in living cells , Results: Lithium reversibly reduced tau phosphorylation at therapeutic conc entrations, and even at high concentrations did nor alter neuronal morpholo gy, Green fluorescent protein tagged-tau when phosphorylated by GSK-3 was d iffusely distributed; treatment with lithium resulted in association with m icrotubules and then bundle formation, Removing lithium allowed observation of the dissolution of bundles and gradual dissociation of tau from microtu bules in living cells, Conclusions: Lithium may have multiple effects in brain, but at least one a ction is demonstrated to be a relative inhibition of GSK-3-induced tall pho sphorylation. These results carry implications for future studies of the ac tions of mood-stabilizing drugs and indeed of the molecular mechanisms of a ffective disorders, (C) 1999 Society of Biological Psychiatry.