title: Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice.
abstract: Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer's disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5-lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid-mediated amyloid β (Ab) formation in vitro. In this article, we investigated the role of this pathway in modulating the development of the corticosteroid-dependent AD-like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for 1 week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO-/-) mice, and its effect on memory, amyloid-β and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Aβ levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF-13, which was specifically associated with an increase in the GSK3β activity. Additionally, dexamethasone-treated mice had a significant increase in the tau insoluble fraction and reduction in the postsynaptic protein PDS-95. By contrast, these modifications were blunted in the 3xTg/5LO-/- mice. Our findings highlight the functional role that 5LO plays in stress-induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor.
authors: Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors: Yash B
authors: YB
authors: Joshi
authors: Jin
authors: J
authors: Chu
authors: Domenico
authors: D
authors: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation; D012995:Solubility; D013315:Stress, Psychological; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016859:Lipoxygenase Inhibitors; C558298:Mapt protein, mouse; D016875:tau Proteins; D003907:Dexamethasone; D001094:Arachidonate 5-Lipoxygenase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: 5-lipoxygenase; Alzheimer's disease; amyloid; glucocorticoid; tau protein; transgenic mouse models
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