title: Amelioration of the Alzheimer's disease phenotype by absence of 12/15-lipoxygenase.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a chronic neurodegenerative disorder whose initiating events are not known. Increasing evidence suggests that oxidative stress and inflammation play a role in its pathogenesis. 12/15 Lipoxygenase (12/15LO) by oxidizing polyunsaturated fatty acids forms hydroperoxyacids, which are potent pro-oxidants and inflammatory mediators. Previously, we reported that this metabolic pathway is increased in AD.
  
  
  METHODS
  Here we explore the effect of genetic deletion of 12/15LO on the AD-like phenotype of the tg2576 transgenic mice.
  
  
  RESULTS
  Genetic absence of this enzyme results in a significant reduction in amyloid-β (Aβ) production and deposition and an improvement of cognitive deficits. In vivo and in vitro studies show that the effect of this enzymatic pathway on amyloidosis is mediated by modulation of Aβ precursor protein processing via the β secretase (BACE) proteolytic cascade, which ultimately results in altered formation of Aβ peptides.
  
  
  CONCLUSIONS
  Our findings support the novel hypothesis that blockade of 12/15LO in the central nervous system by modulating BACE proteolytic pathway could be an effective therapy for prevention or treatment of AD.
authors.affiliation: Department of Pharmacology, Temple University, School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Hengxuan
authors.initials: H
authors.lastname: Yang
authors.forename: Jia-Min
authors.initials: JM
authors.lastname: Zhuo
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.forename: Cinzia
authors.initials: C
authors.lastname: Chinnici
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002461:Cell Line, Transformed; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C475064:12-15-lipoxygenase; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases