Involvement of 5-Lipoxygenase in the Corticosteroid-Dependent Amyloid Beta Formation: In Vitro and In Vivo Evidence

Numerous studies show that high circulating level of glucocorticosteroids is a biochemical characteristic of Alzheimer's disease (AD). These stress hormones can increase the amount of AD-like pathology in animal models of the disease. Since they also up-regulate the 5-Lipoxygenase (5-LO), an enzyme which modulates amyloid beta (Aβ) formation, in the present paper we tested the hypothesis that this enzymatic pathway is involved in the glucocorticoid-induced pro-amyloidotic effect.Incubation of neuronal cells with dexamethasone resulted in a significant increase in 5-LO activity and Aβ formation. By contrast, pharmacological inhibition of 5-LO prevented the dexamethasone-dependent increase in Aβ levels. Mouse embryonic fibroblasts responded with a significant increase in Aβ formation after dexamethasone challenge. However, this effect was abolished when dexamethasone was incubated with fibroblasts genetically deficient for 5-LO. No difference in the glucocorticoid receptor levels was observed between the two groups. Finally, treatment of wild type mice with dexamethasone resulted in a significant increase in endogenous brain Aβ levels, which was prevented in mice genetically lacking 5-LO.These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology