Increased lipid peroxidation in Down's syndrome mouse models
Increased lipid peroxidation in Down's syndrome mouse models
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DOI：
10.1111/j.1471-4159.2009.06294.x
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发表时间：
2009-09-01
影响因子：
4.7
通讯作者：
Yamakawa, Kazuhiro
中科院分区：
文献类型：
--
作者：
Ishihara, Keiichi;Amano, Kenji;Yamakawa, Kazuhiro
氧化应激升高已被认为与唐氏综合征（DS）的特征有关。我们以前报道过Ts 1Cje（一种小鼠遗传性DS模型）胚胎脑培养细胞中的氧化应激增加。然而，由于缺乏体内氧化应激增加的证据，我们在这里研究了脂质过氧化，氧化应激的一个典型标志物，在Ts 1Cje和另一个DS小鼠模型Ts 2Cje与重叠，但更大的三体节段的大脑。在Ts 1Cje和Ts 2Cje脑中，脂质过氧化衍生产物13-hydroperoxy-9 Z，11 E-octadecadienoic acid和4-hydroxy-2-nonenal修饰的蛋白质的积累显著增加。用氧化敏感荧光探针分析还表明，Ts 1Cje脑中活性氧本身增加。然而，电子自旋共振分析的微透析液从海马的Ts 1Cje显示，抗氧化活性不受影响，这表明活性氧的生产加速Ts 1Cje。蛋白质组学方法与质谱鉴定与13-hydroperoxy-9 Z，11 E-十八碳二烯酸和/或4-羟基-2-壬烯醛修饰的蛋白质参与ATP生成，神经元细胞骨架或抗氧化活性。这些蛋白质的结构或功能损伤可能导致DS特征，如Ts 1Cje小鼠中存在的认知障碍。
Elevated oxidative stress has been suggested to be associated with the features of Down's syndrome (DS). We previously reported increased oxidative stress in cultured cells from the embryonic brain of Ts1Cje, a mouse genetic DS model. However, since in vivo evidence for increased oxidative stress is lacking, we here examined lipid peroxidation, a typical marker of oxidative stress, in the brains of Ts1Cje and another DS mouse model Ts2Cje with an overlapping but larger trisomic segment. Accumulations of proteins modified with the lipid peroxidation-derived products, 13-hydroperoxy-9Z,11E-octadecadienoic acid and 4-hydroxy-2-nonenal were markedly increased in Ts1Cje and Ts2Cje brains. Analysis with oxidation-sensitive fluorescent probe also showed that reactive oxygen species themselves were increased in Ts1Cje brain. However, electron spin resonance analysis of microdialysate from the hippocampus of Ts1Cje showed that antioxidant activity remained unaffected, suggesting that the reactive oxygen species production was accelerated in Ts1Cje. Proteomics approaches with mass spectrometry identified the proteins modified with 13-hydroperoxy-9Z, 11E-octadecadienoic acid and/or 4-hydroxy-2-nonenal to be involved in either ATP generation, the neuronal cytoskeleton or antioxidant activity. Structural or functional impairments of these proteins by such modifications may contribute to the DS features such as cognitive impairment that are present in the Ts1Cje mouse.