A role for 12/15 lipoxygenase in the amyloid beta precursor protein metabolism.
12/15 Lipoxygenase (12/15LO) protein levels and activity are increased in pathologically affected regions of Alzheimer's disease (AD) brains, compared with controls. Its metabolic products are elevated in cerebrospinal fluid of patients with AD and individuals with mild cognitive impairment, suggesting that this enzyme may be involved early in AD pathogenesis. Herein, we investigate the effect of pharmacologic inhibition of 12/15LO on the amyloid beta precursor protein (APP) metabolism. To this end, we used CHO and N2A cells stably expressing human APP with the Swedish mutant, and two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC. Our results demonstrated that both drugs dose-dependently reduced Abeta formation without affecting total APP levels. Interestingly, in the same cells we observed a significant reduction in secreted (s)APPbeta and beta-secretase (BACE), but not sAPPalpha and ADAM10 protein levels. Together, these data show for the first time that this enzymatic pathway influences Abeta formation whereby modulating the BACE proteolytic cascade. We conclude that specific pharmacologic inhibition of 12/15LO could represent a novel therapeutic target for treating or preventing AD pathology in humans.
Succol
Francesca
F
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Praticò
Domenico
D
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000502:physiology*; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005449:Fluorenes / Q000494:pharmacology; D006801:Humans; D016859:Lipoxygenase Inhibitors; D009154:Mutation
C475064:12-15-lipoxygenase; C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005449:Fluorenes; D016859:Lipoxygenase Inhibitors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases