Protein-bound acrolein: A novel marker of oxidative stress in Alzheimer's disease
Protein-bound acrolein: A novel marker of oxidative stress in Alzheimer's disease
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DOI：
10.1046/j.1471-4159.1999.0720751.x
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发表时间：
1999-02-01
影响因子：
4.7
通讯作者：
Gibson, GE
中科院分区：
文献类型：
--
作者：
Calingasan, NY;Uchida, K;Gibson, GE
多项证据支持氧化应激（包括脂质过氧化增加）在阿尔茨海默病 (AD) 发病机制中的作用。脂质过氧化会产生各种活性醛，例如 4-羟基壬烯醛 (HNE)，已在 AD 中通过免疫化学方法检测到这种醛，特别是在神经原纤维缠结中，神经原纤维缠结是 AD 大脑中的主要诊断病变之一。最近的一项研究表明，丙烯醛是脂质过氧化的 α,β-不饱和醛产物中反应性最强的，可以快速掺入蛋白质中，生成羰基衍生物，这是蛋白质氧化应激的标志物。目前的研究使用针对丙烯醛修饰的匙孔血蓝蛋白 (KLH) 的抗体来测试 AD 中蛋白质是否发生丙烯醛修饰。双重免疫荧光显示 AD 病例中超过一半的配对螺旋丝 (PHF)-1 标记的神经原纤维缠结具有很强的丙烯醛-KLH 免疫反应性。丙烯醛-KLH 免疫反应性在一些缺乏 PHF-1 阳性神经原纤维缠结的神经元中也很明显。轻度丙烯醛-KLH 免疫反应性发生在淀粉样蛋白-β 核心周围的营养不良神经突中，而淀粉样蛋白-β 核心本身缺乏丙烯醛-KLH 染色。丙烯醛-KLH免疫染色的模式与HNE相似。对照大脑不包含任何丙烯醛-KLH-免疫反应结构。目前的结果表明，蛋白质结合的丙烯醛是蛋白质氧化损伤的有力标志物，并支持脂质过氧化和蛋白质氧化损伤可能在 AD 中神经原纤维缠结的形成和神经元死亡中发挥关键作用的假设。
Several lines of evidence support the role of oxidative stress, including increased lipid peroxidation, in the pathogenesis of Alzheimer's disease (AD). Lipid peroxidation generates various reactive aldehydes, such as 4-hydroxynonenal (HNE), which have been detected immunochemically in AD, particularly in neurofibrillary tangles, one of the major diagnostic lesions in AD brains. A recent study demonstrated that acrolein, the most reactive among the alpha,beta-unsaturated aldehyde products of lipid peroxidation, could be rapidly incorporated into proteins, generating a carbonyl derivative, a marker of oxidative stress to proteins. The current studies used an antibody raised against acrolein-modified keyhole limpet hemocyanin (KLH) to test whether acrolein modification of proteins occurs in AD. Double immunofluorescence revealed strong acrolein-KLH immunoreactivity in more than half of all paired helical filament (PHF)-1-labeled neurofibrillary tangles in AD cases. Acrolein-KLH immunoreactivity was also evident in a few neurons lacking PHF-1-positive neurofibrillary tangles. Light acrolein-KLH immunoreactivity occurred in dystrophic neurites surrounding the amyloid-beta core, which itself lacked acrolein-KLH staining. The pattern of acrolein-KLH immunostaining was similar to that of HNE. Control brains did not contain any acrolein-KLH-immunoreactive structures. The current results suggest that protein-bound acrolein is a powerful marker of oxidative damage to protein and support the hypothesis that lipid peroxidation and oxidative damage to protein may play a crucial role in the formation of neurofibrillary tangles and to neuronal death in AD.