Gene regulation and DNA damage in the ageing human brain
Gene regulation and DNA damage in the ageing human brain
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DOI：
10.1038/nature02661
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发表时间：
2004-06-24
期刊：
影响因子：
64.8
通讯作者：
Yankner, BA
中科院分区：
文献类型：
--
作者：
Lu, T;Pan, Y;Yankner, BA
人脑老化是老年人认知能力下降的原因之一，也是阿尔茨海默病的主要风险因素1。人一生中大脑开始老化的时间是未定的(2-4)。在这里，我们展示了从26岁到106岁的人的额叶皮质的转录图谱定义了一组在40岁后表达减少的基因。这些基因在突触可塑性、囊泡运输和线粒体功能中发挥核心作用。紧随其后的是压力反应、抗氧化剂和DNA修复基因的诱导。在老年皮质中表达降低的基因的启动子中，DNA损伤显著增加。此外，这些基因启动子在培养的人类神经元中受到氧化应激的选择性损伤，并显示出碱基切除DNA修复减少。因此，DNA损伤可能会减少涉及学习、记忆和神经元存活的选择性脆弱基因的表达，启动一项在成年早期就开始的大脑老化计划。
The ageing of the human brain is a cause of cognitive decline in the elderly and the major risk factor for Alzheimer's disease1. The time in life when brain ageing begins is undefined(2-4). Here we show that transcriptional profiling of the human frontal cortex from individuals ranging from 26 to 106 years of age defines a set of genes with reduced expression after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. This is followed by induction of stress response, antioxidant and DNA repair genes. DNA damage is markedly increased in the promoters of genes with reduced expression in the aged cortex. Moreover, these gene promoters are selectively damaged by oxidative stress in cultured human neurons, and show reduced base-excision DNA repair. Thus, DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a programme of brain ageing that starts early in adult life.