Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease
Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease
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DOI：
10.2220/biomedres.30.227
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发表时间：
2009-08-01
影响因子：
1.2
通讯作者：
Ishigami, Akihito
中科院分区：
文献类型：
--
作者：
Fukuda, Mitsugu;Kanou, Fumihisa;Ishigami, Akihito
阿尔茨海默病（AD）是人类进行性认知障碍的最常见原因之一，其特征在于大脑中的神经变性。脂质过氧化被认为在AD的发病机制中起着重要作用。4-羟基壬烯醛（HNE）是多不饱和脂肪酸过氧化反应的产物，它反过来又提供了体内脂质过氧化的证据。HNE与蛋白质组氨酸残基反应形成稳定的HNE-组氨酸迈克尔加合物。为了阐明脂质过氧化作用对AD发病机制的影响，我们测量了HNE-组氨酸迈克尔加合物在从四个AD患者和四个年龄匹配的对照组的腰肌通过半定量免疫组织化学方法使用一种特异性抗体的环状半缩醛型的HNE-组氨酸迈克尔加合物。该抗体不与开环形式的HNE-组氨酸迈克尔加合物和吡咯：形式的HNE-赖氨酸迈克尔加合物反应。HNE加合物在AD和对照供体的脑中均被检测到，尤其是在CA 2、CA 3和CA 4区。AD患者HNE加合物在这些区域的免疫反应强度明显高于对照组。HNE加合物位于海马锥体细胞胞体周围。这些结果表明，AD患者的海马经历脂质过氧化，并暗示这种活性是产生细胞毒性产物如HNE的基础，HNE是AD发病机制的原因。
Alzheimer's disease (AD) is among the most common causes of progressive cognitive impairment in humans and is characterized by neurodegeneration in the brain. Lipid peroxidation is thought to play a rote in the pathogenesis of AD. 4-hydroxynonenal (HNE) results from peroxidation of polyunsaturated fatty acids and it in turn gives evidence of lipid peroxidation in vivo. HNE reacts with protein histidine residue to form a stable HNE-histidine Michael adduct. To clarify the influence of lipid peroxidation on the pathogenesis of AD, we measured HNE-histidine Michael adduct in hippocampi from four AD patients and four age-matched controls by means of semiquantitative immunohistochemistry using a specific antibody to cyclic hemiacetal type of HNE-histidine Michael adduct. This antibody does not react with the ring-opened form of HNE-histidine Michael adduct and the pyrrole :form of HNE-lysine Michael adduct. The HNE adduct was detected in the hippocampi of both AD and control donors, especially in the CA2, CA3 and CA4 sectors. Immunoreactive intensity of HNE adduct in these sectors were significantly higher in AD patients than in the controls. The HNE adduct was found in the perikarya of pyramidal cells in the hippocampus. These results show that the hippocampi of patients with AD undergo lipid peroxidation and imply that this activity underlies the production Of cytotoxic products such as HNE that are responsible for the pathogenesis of AD.