Abstract
BackgroundNumerous 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.Methodology/Principal FindingsIncubation 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.ConclusionsThese findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology.
Highlights
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease with dementia in the elderly, affecting approximately 6–8% all persons aged .65 years [1]
These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology
Dexamethasone induced a significant increase in amyloid beta (Ab) 1–40 and 1–42 levels (Fig. 2A,B), which was associated with a significant elevation in the production of leukotriene B4 (LTB4), the major metabolic product of 5-LO activation (Fig. 2C)
Summary
Alzheimer’s disease (AD) is the most common form of neurodegenerative disease with dementia in the elderly, affecting approximately 6–8% all persons aged .65 years [1]. We sought to determine whether 5LO was involved in the glucocorticoid-dependent Ab elevation To this end, we investigated the effect of dexamethasone on Ab formation and metabolism in the presence and in the absence of 5LO enzymatic activity in vitro and in vivo. 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 up-regulate the 5-Lipoxygenase (5-LO), an enzyme which modulates amyloid beta (Ab) formation, in the present paper we tested the hypothesis that this enzymatic pathway is involved in the glucocorticoid-induced pro-amyloidotic effect
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