Involvement of 5-lipoxygenase in the corticosteroid-dependent amyloid beta formation: in vitro and in vivo evidence.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Simone
S
Puccio
Jin
J
Chu
Domenico
D
Praticò
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000544:Alzheimer Disease / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000502:physiology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
D000305:Adrenal Cortex Hormones; D016564:Amyloid beta-Protein Precursor; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase
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