Abstract
Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.
Highlights
Glycogen synthase kinase-3 (GSK-3) was initially identified more than two decades ago as an enzyme involved in the control of glycogen metabolism (Cohen, 1979; Embi et al, 1980)
This study revealed that apoptosis induced by the extrinsic pathway, by Fas receptor signaling, was enhanced by lithium and other GSK-3 inhibitors (Song et al, 2004)
What we can extract from studies in Tet/GSK-3β is that an increase in GSK-3 activity correlates with an increase in apoptosis which seems to involve tau modification, as seen when mice were combined with models of tau modifications
Summary
Glycogen synthase kinase-3 (GSK-3) was initially identified more than two decades ago as an enzyme involved in the control of glycogen metabolism (Cohen, 1979; Embi et al, 1980). They show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, further supporting the potential of GSK-3 inhibitors for AD therapeutics (Engel et al, 2006b).
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