GSK-3 inhibitors for Alzheimer’s disease

Abstract

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.

Keywords::

• Alzheimer’s disease
• amyloid peptide
• GSK-3
• lithium
• tau

Financial & competing interests disclosure

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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.