In Alzheimer's disease, tau protein becomes hyperphosporylated, which can contribute to neuronal degeneration. However, the implicated protein kinases are still unknown. Now we report that lithium (an inhibitor of glycogen synthase kinase‐3) causes tau dephosphorylation at the sites recognized by antibodies Tau‐1 and PHF‐1 both in cultured neurons and in vivo in rat brain. This is consistent with a major role for glycogen synthase kinase‐3 in modifying proline‐directed sites on tau protein within living neurons under physiological conditions. Lithium also blocks the Alzheimer's disease‐like proline‐directed hyperphosphorylation of tau protein which is observed in neurons treated with a phosphatase inhibitor. These data raise the possibility of using lithium to prevent tau hyperphosphorylation in Alzheimer's disease.

The deposition of L L-amyloid peptide (AL L), the hyperphosphorylation of tau protein and the death of neurons in certain brain regions are characteristic features of Alzheimer's disease. It has been proposed that the accumulation of aggregates of AL L is the trigger of neurodegeneration in this disease. In support of this view, several studies have demonstrated that the treatment of cultured neurons with AL L leads to the hyperphosphorylation of tau protein and neuronal cell death. Here we report that lithium prevents the enhanced phosphorylation of tau protein at the sites recognized by antibodies Tau-1 and PHF-1 which occurs when cultured rat cortical neurons are incubated with AL L. Interestingly, lithium also significantly protects cultured neurons from AL L-induced cell death. These results raise the possibility of using chronic lithium treatment for the therapy of Alzheimer's disease.z 1999 Federation of European Biochemical Societies.

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of the beta-amyloid peptide and the hyperphosphorylation of the tau protein, among other features. The most widely accepted hypothesis on the etiopathogenesis of this disease proposes that the aggregates of the beta-amyloid peptide are the main triggers of tau hyperphosphorylation and the subsequent degeneration of affected neurons. In support of this view, fibrillar aggregates of synthetic beta-amyloid peptide induce tau hyperphosphorylation and cell death in cultured neurons. We have previously reported that lithium inhibits tau hyperphosphorylation and also significantly protects cultured neurons from cell death triggered by beta-amyloid peptide. As lithium is a relatively specific inhibitor of glycogen synthase kinase-3 (in comparison with other protein kinases), and other studies also point to a relevant role of this enzyme, we favor the view that glycogen synthase kinase-3 is a crucial element in the pathogenesis of Alzheimer's disease. In our opinion, the possibility of using lithium, or other inhibitors of glycogen synthase kinase-3, in experimental trials aimed to ameliorate neurodegeneration in Alzheimer's disease should be considered.