Lithium protects cultured neurons against beta-amyloid-induced neurodegeneration.

The deposition of beta-amyloid peptide (A beta), 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 A beta is the trigger of neurodegeneration in this disease. In support of this view, several studies have demonstrated that the treatment of cultured neurons with A beta 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 A beta. Interestingly, lithium also significantly protects cultured neurons from A beta-induced cell death. These results raise the possibility of using chronic lithium treatment for the therapy of Alzheimer's disease.

Downregulation of glycogen synthase kinase-3beta (GSK-3beta) protein expression during neuroblastoma IMR-32 cell differentiation.

Glycogen synthase kinase-3gamma (GSK-3beta) is a multifunctional protein kinase that phosphorylates a variety of substrates including the neuronal-specific microtubule-associated protein tau. Here we report that the down-regulation of the GSK-3beta protein is an early event in the course of the differentiation of human neuroblastoma IMR-32 cells. This decline in GSK-3beta is accompanied by a significant decrease in the phosphorylation state of tau protein. A noteworthy increase in tau protein expression also takes place later during the differentiation of IMR-32 cells. The augmented expression and diminished phosphorylation of tau protein in differentiated IMR-32 cells can be correlated with increments in the assembly of microtubules and in the association of tau with microtubules. These results suggest a contribution of a decrease in GSK-3beta to molecular events leading to neuroblastoma cell differentiation. Among these, tau protein dephosphorylation might favor microtubule stabilization within neurites.

Lithium inhibits Alzheimer's disease-like tau protein phosphorylation in neurons.

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.

Glycogen synthase kinase 3 phosphorylation of different residues in the presence of different factors: analysis on tau protein.

Several peptides derived from microtubule-associated tau protein, have been tested as substrates for glycogen synthase kinase 3 (GSK 3). In the absence of cofactors, GSK 3 can modify serines or threonines followed by prolines. In other cases, a phosphorylation in position +4 is required for the phosphorylation of threonine/serine residues. A third type of substrate can be modified by GSK 3 in the presence of heparin. The comparison of GSK 3 with other kinases suggests some similar features of this kinase with proline-directed protein kinases, such as cdc-2 or mitogen-activated protein kinase (MAP Kinases,) and also with casein kinase 2 (CK 2). Thus, all these kinases are specifically inhibited by 5,6-Dichloro-1-(beta-D-ribofuranosyl)-benzimidazole (DRB). However, heparin is an inhibitor of CK 2 whereas it activates the modification of certain substrates by GSK 3. A possible explanation for the obtained results is that the consensus sequence for GSK 3 phosphorylation is a serine/threonine adjacent to a proline or other beta-turn former residue and that such recognition could be favoured by the presence of adjacent negative charges or the addition of polyanions.