title: Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice.
abstract: The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: J-G
authors.initials: JG
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Giannopoulos
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Blass
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Childers
authors.affiliation: Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Abou-Gharbia
authors.affiliation: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003213:Conditioning, Psychological / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005239:Fear / Q000187:drug effects; D005449:Fluorenes / Q000627:therapeutic use*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: 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; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase