GSK-3 inhibitors for Alzheimer's disease

Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer’s disease, the extracellular senile plaques made of β-amyloid and the intracellular neurofibrillary tangles made of hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of β-amyloid as well as to respond to this peptide. The use of several transgenic models overexpressing 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 has been demonstrated to prevent tau phosphorylation. In this 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.This work was supported by grants from Neuropharma, Fundación Botín, Spanish CICYT, Comunidad de Madrid (NEURODEGMODELS-CM), CIBER on Neurodegeneration and by institutional grants from Fundación Ramón Areces.Peer reviewe