Department of Pharmacology, Temple University, School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Biol Psychiatry. 2010 Nov 15;68(10):922-9. doi: 10.1016/j.biopsych.2010.04.010. Epub 2010 Jun 8.
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.
Here we explore the effect of genetic deletion of 12/15LO on the AD-like phenotype of the tg2576 transgenic mice.
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.
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.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，其起始事件尚不清楚。越来越多的证据表明，氧化应激和炎症在其发病机制中起作用。12/15 脂氧合酶（12/15LO）通过氧化多不饱和脂肪酸形成过氧酸，过氧酸是一种有效的促氧化剂和炎症介质。此前，我们报道过这种代谢途径在 AD 中增加。
在这里，我们探讨了基因敲除 12/15LO 对 tg2576 转基因小鼠类似 AD 表型的影响。
该酶的遗传缺失导致淀粉样蛋白-β（Aβ）产生和沉积显著减少，认知缺陷得到改善。体内和体外研究表明，这种酶促途径对淀粉样变性的影响是通过调节 Aβ前体蛋白加工来介导的，通过β分泌酶（BACE）蛋白水解级联，最终导致 Aβ肽形成的改变。
我们的发现支持了一个新的假设，即通过调节 BACE 蛋白水解途径阻断中枢神经系统中的 12/15LO 可能是预防或治疗 AD 的有效治疗方法。
