University of Kansas Alzheimer's Disease Research Center, Kansas City, KS 66205, USA.
Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Int J Mol Sci. 2024 Jul 16;25(14):7774. doi: 10.3390/ijms25147774.
DNA strand breaks excessively accumulate in the brains of patients with Alzheimer's disease (AD). While traditionally considered random, deleterious events, neuron activity itself induces DNA breaks, and these "adaptive" breaks help mediate synaptic plasticity and memory formation. Recent studies mapping the brain DNA break landscape reveal that despite a net increase in DNA breaks in ectopic genomic hotspots, adaptive DNA breaks around synaptic genes are lost in AD brains, and this is associated with transcriptomic dysregulation. Additionally, relationships exist between mitochondrial dysfunction, a hallmark of AD, and DNA damage, such that mitochondrial dysfunction may perturb adaptive DNA break formation, while DNA breaks may conversely impair mitochondrial function. A failure of DNA break physiology could, therefore, potentially contribute to AD pathogenesis.
阿尔茨海默病（AD）患者的大脑中，DNA 链断裂过度积累。虽然传统上认为这是随机的、有害的事件，但神经元活动本身会诱导 DNA 断裂，而这些“适应性”断裂有助于介导突触可塑性和记忆形成。最近的研究绘制了大脑 DNA 断裂景观图，揭示了尽管在异位基因组热点处总的 DNA 断裂增加，但 AD 大脑中围绕突触基因的适应性 DNA 断裂丢失了，这与转录组失调有关。此外，线粒体功能障碍（AD 的一个标志）与 DNA 损伤之间存在关系，使得线粒体功能障碍可能扰乱适应性 DNA 断裂的形成，而 DNA 断裂反过来又可能损害线粒体功能。因此，DNA 断裂生理学的失败可能会导致 AD 的发病机制。
