期刊
BIOLOGICAL PSYCHIATRY
卷 68, 期 10, 页码 922-929出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2010.04.010
关键词
Alzheimer's disease; amyloid beta; lipoxygenase; transgenic animal models
资金
- Alzheimer's Association [ZEN 07-59289]
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 beta (A beta) production and deposition and an improve nient of cognitive deficits In vivo and in vitro studies show that the effect of this enzymatic pathway on amyloidosis is mediated by modulation of A beta precursor protein processing via the beta secretase (BACE) proteolytic cascade which ultimately results in altered formation of A beta 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
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