Changes in neuronal DNA content variation in the human brain during aging
Changes in neuronal DNA content variation in the human brain during aging
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DOI：
10.1111/j.1474-9726.2012.00826.x
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发表时间：
2012-08-01
期刊：
影响因子：
7.8
通讯作者：
Arendt, Thomas
中科院分区：
文献类型：
--
作者：
Fischer, Hans-Georg;Morawski, Markus;Arendt, Thomas
人类大脑被认为是一个遗传镶嵌体，包含少量但恒定数量的神经元，其DNA量超过二倍体水平，这些神经元最初似乎是通过各种染色体分离缺陷产生的。虽然这些细胞的一部分在发育过程中明显死亡，但在成熟的大脑中已经发现了染色体拷贝数异常的神经元。这种基因组改变可能导致染色体不稳定，影响神经元的活力，从而可能导致与年龄有关的精神障碍。然而，在成年和衰老的大脑中，具有这种结构基因组变异的神经元的频率变化是未知的。在这里，我们量化了正常人脑大脑皮层中具有超过二倍体DNA含量的神经元的频率，并分析了其在生命的第四和第九个十年之间的变化。我们应用了一种基于载玻片的细胞术方案，该方案针对单个识别的神经元的DNA定量进行了优化，这允许分析每个大脑约500 000个神经元的DNA含量。平均而言，11.5%的皮质神经元显示DNA含量高于二倍体水平。具有这种基因组改变的神经元的频率在年轻时最高，并随着年龄的增长而下降。我们的研究结果表明，与DNA含量超过二倍体水平相关的基因组变异可能会损害这些神经元在衰老大脑中的生存能力，从而可能有助于与年龄相关的CNS疾病的易感性。或者，需要考虑健康老龄化大脑的潜在选择偏差，假设DNA含量变化超过一定阈值与阿尔茨海默病相关。
The human brain has been proposed to represent a genetic mosaic, containing a small but constant number of neurons with an amount of DNA exceeding the diploid level that appear to be generated through various chromosome segregation defects initially. While a portion of these cells apparently die during development, neurons with abnormal chromosomal copy number have been identified in the mature brain. This genomic alteration might to lead to chromosomal instability affecting neuronal viability and could thus contribute to age-related mental disorders. Changes in the frequency of neurons with such structural genomic variation in the adult and aging brain, however, are unknown. Here, we quantified the frequency of neurons with a more than diploid DNA content in the cerebral cortex of normal human brain and analyzed its changes between the fourth and ninth decades of life. We applied a protocol of slide-based cytometry optimized for DNA quantification of single identified neurons, which allowed to analyze the DNA content of about 500 000 neurons for each brain. On average, 11.5% of cortical neurons showed DNA content above the diploid level. The frequency of neurons with this genomic alteration was highest at younger age and declined with age. Our results indicate that the genomic variation associated with DNA content exceeding the diploid level might compromise viability of these neurons in the aging brain and might thus contribute to susceptibilities for age-related CNS disorders. Alternatively, a potential selection bias of healthy aging brains needs to be considered, assuming that DNA content variation above a certain threshold associates with Alzheimer's disease.