Role of glycogen synthase kinase-3 in Alzheimer's disease pathogenesis and glycogen synthase kinase-3 inhibitors

Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer's disease, the extracellular senile plaques composed of beta-amyloid and the intracellular neurofibrillary tangles formed from hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of the tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of amyloid-beta, as well as to respond to this peptide. In several transgenic models, overexpression of GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and it has been demonstrated that this is able to prevent tau phosphorylation. In the present review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer's disease therapy, as well as some of their potential problems.