12/15-Lipoxygenase is increased in Alzheimer's disease -: Possible involvement in brain oxidative stress
12/15-Lipoxygenase is increased in Alzheimer's disease -: Possible involvement in brain oxidative stress
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DOI：
10.1016/s0002-9440(10)63724-8
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发表时间：
2004-05-01
影响因子：
6
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Praticò, D;Zhukareva, V;Lee, VMY
阿尔茨海默病 (AD) 是一种损害认知和行为的慢性神经退行性疾病。尽管起始分子事件尚不清楚，但越来越多的证据表明氧化应激可能在其发病机制中发挥功能性作用。脂氧合酶 (LOX) 通过氧化多不饱和脂肪酸合成氢过氧酸，氢过氧酸是有效的促氧化介质。由于间接证据表明 12/15-LOX 是氧化应激的主要来源，因此我们研究了经组织病理学证实的 AD 病例和对照病例的不同大脑区域中该酶的蛋白质水平和活性。使用定量蛋白质印迹分析，我们证明在 AD 大脑受影响的额叶和颞区中，12/15-LOX 的量高于对照组，而在小脑中未检测到两组之间的差异。这一观察结果得到了免疫组织化学研究的证实。与对照组相比，AD 大脑中 12/15-LOX 的代谢产物 12/15-羟基二十碳四烯酸的水平也显着升高。这种增加与脑脂质过氧化直接相关，与维生素 E 水平成反比。最后，在体外对该酶进行基因删除，导致与 H2O2 或淀粉样蛋白 β 孵育后细胞氧化应激反应减少。这些数据表明，12/15-LOX 代谢途径增加，并与 AD 大脑中的氧化失衡相关，这意味着这种酶可能与这种神经退行性疾病的发病机制有关。
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that oxidative stress could play a functional role in its pathogenesis. Lipoxygenase (LOX) enzymes by oxidizing polyunsaturated fatty acids synthesize hydroperoxyacids, which are potent pro-oxidant mediators. Because circumstantial evidence suggests that 12/15-LOX is a major source of oxidative stress, we investigated the protein levels and activity of this enzyme in different brain regions of histopathologically confirmed AD and control cases. Using quantitative Western blot analysis we demonstrated that in affected frontal and temporal regions of AD brains the amount of 12/15-LOX was higher compared with controls, whereas no difference between the two groups was detected in the cerebellum. This observation was confirmed by immunohistochemical studies. Levels of 12/15-hydroxyeicosatetraenoic acids, metabolic products of 12/15-LOX, were also markedly elevated in AD brains compared to controls. This increase directly correlated with brain lipid peroxidation, and inversely with vitamin E levels. Finally, genetic deletion of this enzyme in vitro resulted in a reduction of the cellular oxidative stress response after incubation with H2O2 or amyloid beta. These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder.