Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Int J Mol Sci. 2022 Jul 28;23(15):8352. doi: 10.3390/ijms23158352.
DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.
DNA 双链断裂（DSBs），根据修复的复杂性被归类为最有害的 DNA 损伤类型，会导致细胞凋亡或肿瘤发生。在衰老过程中，DNA 损伤增加，而 DNA 修复减少。在疾病中，这种情况会加剧，因为从被诊断为轻度认知障碍（MCI）或阿尔茨海默病（AD）的患者的死后组织中显示出增加的 DSB。DSB 在即时早期基因（IEG）表达、学习和记忆中的新作用已被提出。诱导神经元活动会导致 DSB 增加和 IEG 上调，而增加 DSB 并抑制 DSB 修复会损害长期记忆并改变 IEG 表达。与这种模式一致，携带显性 AD 突变的小鼠具有增加的基线 DSB，并且观察到 DSB 修复受损。这些数据表明 DSB 在中枢神经系统中具有适应性作用，而 DSB 的失调和/或修复可能会导致与年龄相关的认知衰退（ACD）、MCI 和 AD。在这篇综述中，我们讨论了 DSB 在海马依赖性学习、记忆和 IEG 表达中的适应性作用。我们总结了 IEG、DSB 的历史以及 DSB 在突触可塑性、衰老和 AD 中的作用。DSB 在大脑中可能具有适应性功能，即使它们的形成和修复稍有改变，也可能改变 IEG、学习和记忆。
