Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair
Accelerated Age-Related Cognitive Decline and Neurodegeneration, Caused by Deficient DNA Repair
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DOI：
10.1523/jneurosci.1589-11.2011
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发表时间：
2011-08-31
影响因子：
5.3
通讯作者：
Elgersma, Ype
中科院分区：
文献类型：
--
作者：
Borgesius, Nils Z.;de Waard, Monique C.;Elgersma, Ype
随着人口老龄化，与糖尿病相关的认知能力下降和神经退行性疾病对我们的社会来说是一个日益严峻的挑战。DNA损伤的积累被认为是导致这些损伤的原因，但缺乏DNA损伤导致神经元可塑性和记忆受损的直接证据。在这里，我们利用Ercc 1（Delta/-）突变小鼠，这是受损的DNA核苷酸切除修复，链间交联修复，双链断裂修复。我们发现，这些小鼠表现出神经元可塑性和渐进性神经元病理学的年龄依赖性下降，提示神经退行性过程。在小鼠中观察到类似的表型，其中突变仅限于兴奋性前脑神经元。此外，这些神经元特异性突变体发展为学习障碍。总之，这些结果表明未修复的累积DNA损伤与年龄依赖性认知衰退和神经退行性变之间存在因果关系。因此，累积的DNA损伤可能是与年龄相关的认知能力下降和神经退行性疾病的发病和进展的重要因素。
Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1(Delta/-) mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an age-dependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases.