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.
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: Anca D Dobrian; David C Lieb; Banumathi K Cole; David A Taylor-Fishwick; Swarup K Chakrabarti; Jerry L Nadler Journal: Prog Lipid Res Date: 2010-10-21 Impact factor: 16.195
Authors: J Chu; J-G Li; P F Giannopoulos; B E Blass; W Childers; M Abou-Gharbia; D Praticò Journal: Mol Psychiatry Date: 2015-01-06 Impact factor: 15.992
Authors: Haley C Dunn; Rahasson R Ager; David Baglietto-Vargas; David Cheng; Masashi Kitazawa; David H Cribbs; Rodrigo Medeiros Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472