Increased nuclear DNA oxidation in the brain in Alzheimer's disease
Increased nuclear DNA oxidation in the brain in Alzheimer's disease
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DOI：
10.1046/j.1471-4159.1998.71052034.x
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发表时间：
1998-11-01
影响因子：
4.7
通讯作者：
Markesbery, WR
中科院分区：
文献类型：
--
作者：
Gabbita, SP;Lovell, MA;Markesbery, WR
多种证据表明，氧化应激是阿尔茨海默病（AD）神经元死亡的一个因素。DNA发生的氧化损伤可能在正常衰老和神经退行性疾病（包括AD）中发挥作用。这是一项关于发生在AD患者和认知完整的、前瞻性评估的、年龄匹配的对照受试者大脑中的核DNA中的氧化损伤的研究。从11名对照组和9名AD组中分离出额叶、颞叶、顶叶和小脑的核DNA，并使用气相色谱/质谱法对氧化嘌呤和嘧啶碱基进行定量。使用稳定同位素标记的氧化碱基类似物作为内标物来测量5-羟基尿嘧啶、5-羟基胞嘧啶、8-羟基腺嘌呤、4，6-二氨基-5-甲酰胺基嘧啶（Fapy-腺嘌呤）、8-羟基鸟嘌呤和2，6-二氨基-4-羟基-5-甲酰胺基嘧啶（Fapy-鸟嘌呤）。与对照受试者相比，在AD脑中发现5-羟基胞嘧啶、5-羟基尿嘧啶、8-羟基腺嘌呤和8-羟基鸟嘌呤的统计学显著升高（p < 0.05）。有一个增加的趋势，在AD脑中的Fappy-腺嘌呤的水平，和Fappy-鸟嘌呤显示出更高的水平，在对照组的大脑相比，AD的趋势。新皮质区域的DNA氧化损伤水平通常高于小脑。氧化型碱性磷酸酶与神经纤维缠结和老年斑计数之间无显著相关性。我们的研究结果表明，核DNA损伤的氧衍生的自由基增加，在AD和支持的概念，大脑是下增加的氧化应激在AD。
Multiple lines of evidence indicate that oxidative stress is a contributor to neuronal death in Alzheimer's disease (AD). The oxidative damage that occurs to DNA may play a role in both normal aging and neurodegenerative diseases, including AD. This is a study of the oxidative damage that occurs in nuclear DNA in the brains of AD patients and cognitively intact, prospectively evaluated, age-matched control subjects. Nuclear DNA from frontal, temporal, and parietal lobes and cerebellum was isolated from 11 control subjects and 9 AD subjects, and oxidized purine and pyrimidine bases were quantitated using gas chromatography/mass spectrometry. Stable isotope-labeled oxidized base analogues were used as internal standards to measure 5-hydroxyuracil, 5-hydroxycytosine, 8-hydroxyadenine, 4,6-diamino-5-formamidopyrimidine (Fapy-adenine), 8-hydroxyguanine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-guanine). Statistically significant elevations of 5-hydroxycytosine, 5-hydroxyuracil, 8-hydroxyadenine, and 8-hydroxyguanine were found in AD brain compared with control subjects (p < 0.05). There was an increased trend in the levels of Fapy-adenine in the AD brain, and Fapy-guanine showed a trend toward higher levels in control brains compared with AD. A generally higher level of oxidative DNA damage was present in neocortical regions than cerebellum. No significant correlation was observed between the oxidized bases and neurofibrillary tangle and senile plaque counts. Our results demonstrate that nuclear DNA damage by oxygen-derived radicals is increased in AD and support the concept that the brain is under increased oxidative stress in AD.