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 beta-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 beta-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.
Avila
Jesús
J
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. javila@cbm.uam.es
Hernández
Félix
F
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*
D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3