Department of Neuroscience, University of Pisa, Pisa, Italy.
J Alzheimers Dis. 2010;20(4):953-66. doi: 10.3233/JAD-2010-1415.
Increasing evidence suggests that the repair of DNA lesions, particularly oxidative DNA lesions, might be compromised in Alzheimer's disease (AD). Studies performed in brains and peripheral tissues of both AD patients and individuals affected by mild cognitive impairment (MCI) revealed that oxidative DNA damage is one of the earliest detectable events during the progression from healthy aging to dementia. Moreover, the increase in DNA damage is paralleled by a decrease in DNA repair activities. Several hypotheses are currently tested in order to explain the decreased DNA repair activity observed in MCI and AD subjects. Some authors have suggested that mutations or polymorphisms in DNA repair genes might impair DNA repair. However, this hypothesis does not seem to be confirmed by recent genetic association studies. Others suggest that DNA repair proteins might be inactivated by oxidative induced post-translational modifications or degradation. There is also indication that different isoforms of the same repair protein might be involved in the progression from early to late stages AD. Moreover, a widespread activation of DNA repair pathways might generate death signals ending with neuronal apoptosis. A link between environmental induced epigenetic modification, oxidation, and repair of AD related genes has been also proposed. Most of these studies have been performed during the last few years, and we are still at the beginning of understanding the complex interplay between oxidative DNA damage, DNA repair, and neuronal death in the brain leading to Alzheimer's dementia, making this topic an exciting and promising field for future investigation.
越来越多的证据表明，阿尔茨海默病（AD）患者的 DNA 损伤修复，尤其是氧化损伤修复，可能受损。在 AD 患者和轻度认知障碍（MCI）患者的大脑和外周组织中进行的研究表明，氧化 DNA 损伤是从健康衰老到痴呆进展过程中最早可检测到的事件之一。此外，DNA 损伤的增加伴随着 DNA 修复活性的降低。目前正在测试几种假说，以解释在 MCI 和 AD 患者中观察到的 DNA 修复活性降低。一些作者认为，DNA 修复基因的突变或多态性可能会损害 DNA 修复。然而，最近的遗传关联研究似乎并没有证实这一假设。其他人则认为，氧化诱导的翻译后修饰或降解可能使 DNA 修复蛋白失活。也有迹象表明，同一修复蛋白的不同同工型可能参与了从早期到晚期 AD 的进展。此外，不同 DNA 修复途径的广泛激活可能会产生死亡信号，最终导致神经元凋亡。还提出了环境诱导的表观遗传修饰、氧化和 AD 相关基因修复之间的联系。这些研究中的大多数是在过去几年中进行的，我们仍处于理解氧化 DNA 损伤、DNA 修复和导致阿尔茨海默病痴呆的神经元死亡之间复杂相互作用的开始阶段，使这一主题成为未来研究的一个令人兴奋和有前途的领域。
