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

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 composed of β-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-β, 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.

Keywords::

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

Financial & competing interests disclosure

This study was funded by grants from the Spanish Ministry of Health (SAF 2006-02424), Ciberned (CB06/05/0035), Noscira (2008/285), Comunidad de Madrid (SAL/0202/2006), Fundación Marcelino Botín, Fundación CIEN (PI 008/09) and an institutional grant from Fundación Ramón Areces. Francisco Wandosell was supported by grants from Ciberned (an initiative of the ISCIII), the Plan Nacional DGCYT SAF2009-12249-C02-01 and CDTI-CENIT-INGENIO 2010 ‘Consorcio MELIUS’; and grant EU-FP7-2009-CT222887, and by an Institutional grant from the ‘Fundación Areces’. None of the funding organizations had any further role in the study design, in the collection, analysis or interpretation of data, in the writing of the report or in the decision to submit the paper for publication. 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.