Yurov Yuri B, Vorsanova Svetlana G, Liehr Thomas, Kolotii Alexei D, Iourov Ivan Y
Mental Health Research Center, Russian Academy of Medical Sciences, 117152 Moscow, Russia.
Mol Cytogenet. 2014 Mar 6;7(1):20. doi: 10.1186/1755-8166-7-20.
Although the link between brain aging and Alzheimer's disease (AD) is a matter of debate, processes hallmarking cellular and tissue senescence have been repeatedly associated with its pathogenesis. Here, we have studied X chromosome aneuploidy (a recognized feature of aged cell populations) in the AD brain.
Extended molecular neurocytogenetic analyses of X chromosome aneuploidy in 10 female AD as well as 10 age and sex matched female control postmortem brain samples was performed by multiprobe/quantitative FISH. Additionally, aneuploidy rate in the brain samples of 5 AD and as 5 age and sex matched control subjects were analyzed by interphase chromosome-specific multicolor banding (ICS-MCB). Totally, 182,500 cells in the AD brain and 182,500 cells in the unaffected brain were analyzed. The mean rate of X chromosome aneuploidy in AD samples was approximately two times higher than in control (control: mean - 1.32%, 95% CI 0.92- 1.71%; AD: mean - 2.79%, 95% CI 1.88-3.69; P = 0.013). One AD sample demonstrated mosaic aneuploidy of chromosome X confined to the hippocampus affecting about 10% of cells. ICS-MCB confirmed the presence of X chromosome aneuploidy in the hippocampal tissues of AD brain (control: mean - 1.74%, 95% CI 1.38- 2.10%; AD: mean - 4.92%, 95% CI 1.14-8.71; P < 0.001).
Addressing X chromosome number variation in the brain, we observed that somatically acquired (post-zygotic) aneuploidy causes large-scale genomic alterations in neural cells of AD patients and, therefore, can be involved in pathogenesis of this common neurodegenerative disorder. In the context of debates about possible interplay between brain aging and AD neurodegeneration, our findings suggest that X chromosome aneuploidy can contribute to both processes. To this end we conclude that mosaic aneuploidy in the brain is a new non-heritable genetic factor predisposing to AD.
尽管脑衰老与阿尔茨海默病（AD）之间的联系仍存在争议，但细胞和组织衰老的标志性过程已多次被认为与其发病机制有关。在此，我们研究了AD脑中的X染色体非整倍体（一种衰老细胞群体的公认特征）。
通过多探针/定量荧光原位杂交技术，对10例女性AD患者以及10例年龄和性别匹配的女性对照者的死后脑样本进行了X染色体非整倍体的扩展分子神经细胞遗传学分析。此外，通过间期染色体特异性多色带分析（ICS-MCB）对5例AD患者和5例年龄和性别匹配的对照者脑样本中的非整倍体率进行了分析。总共分析了AD脑中的182,500个细胞和未受影响脑中的182,500个细胞。AD样本中X染色体非整倍体的平均率约为对照组的两倍（对照组：平均值-1.32%，95%置信区间0.92-1.71%；AD组：平均值-2.79%，95%置信区间1.88-3.69；P = 0.013）。一个AD样本显示局限于海马体的X染色体镶嵌非整倍体，影响约10%的细胞。ICS-MCB证实了AD脑海马组织中存在X染色体非整倍体（对照组：平均值-1.74%，95%置信区间1.38-2.10%；AD组：平均值-4.92%，95%置信区间1.14-8.71；P < 0.001）。
针对脑中X染色体数量变异，我们观察到体细胞获得性（合子后）非整倍体导致AD患者神经细胞发生大规模基因组改变，因此可能参与这种常见神经退行性疾病的发病机制。在关于脑衰老与AD神经退行性变之间可能相互作用的争论背景下，我们的研究结果表明X染色体非整倍体可能对这两个过程都有影响。为此，我们得出结论，脑中的镶嵌非整倍体是一种新的非遗传性遗传因素，易导致AD。
