GLYCOGEN SYNTHASE KINASE-3beta ACTIVITY IS REGULATED BY PRODUCTS OF LIPID PEROXIDATION: RELEVANCE TO ALZHEIMER DISEASE

Glycogen synthase kinase-3beta (GSK3b), a constitutively active serine/threonine kinase initially described as a key enzyme involved in glycogen metabolism, is now known to regulate a diverse array of cell functions. GSK3β activity is regulated by phosphorylation and is a critical downstream element of the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinases (MAPKs) signaling pathways. Deregulation of GSK3b activity, as well as the up-stream signaling pathways involved in its regulation, have been implicated in different diseases including neurodegenerative diseases, such as Alzheimer’s disease (AD). Importantly, in AD, there is a significant increase of oxidative stress-related lipid peroxidation aldehydic products such as 4-hydroxynonenal (HNE) that are thought to play a key role in disease pathogenesis. While the involvement of lipid peroxidation in neuronal cell death is increasingly appreciated, the impact of subtoxic levels of oxidative stress on neuronal function is largely unknown. To further analyze this, as well as the relationship between oxidative stress and GSK3b, in this study we examined the effects of a single exposure of human neuroblastoma IMR-32 cells to HNE on GSK3b phospho-dependent activity and on intracellular signaling cascades that may regulate its phosphorylation state. We provide evidence for a crucial role of the PI3K/AKT and ERK2 pathways as intracellular targets of HNE that mediate the inhibition of GSK3b activity in regulating cellular response to HNE in viable cells under conditions in which membrane lipid peroxidation occurs. These data support a key role for GSK3b as a mediator of the signaling pathways activated by oxidative stress, and therefore it may be included among the redox-sensitive enzymes. These findings provide a key link between oxidative stress and abnormal phosphorylation in AD.