Epigenetic changes in Alzheimer's disease: decrements in DNA methylation.
Epigenetic changes in Alzheimer's disease: decrements in DNA methylation.
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DOI：
10.1016/j.neurobiolaging.2008.12.005
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发表时间：
2010-12
影响因子：
4.2
通讯作者：
Rogers, Joseph
中科院分区：
文献类型：
--
作者：
Mastroeni, Diego;Grover, Andrew;Delvaux, Elaine;Whiteside, Charisse;Coleman, Paul D.;Rogers, Joseph
DNA甲基化是表观遗传机制的重要组成部分，它协调多个基因的变化，并有助于调节所有已知脊椎动物的基因表达。我们评估了内嗅皮层第二层中两个DNA甲基化标记物和八个甲基化维持因子的免疫反应性，该区域表现出大量的阿尔茨海默病（AD）病理学，其中多种基因的表达变化已被报道。我们第一次显示，所有10个表观遗传标记和因子的神经元免疫反应性，在AD病例中有非常显著的下降。这些递减在PHF 1/PS396免疫反应性神经元缠结轴承神经元中特别明显。此外，两个DNA甲基化维持因子，DNMT 1和MBD 2，也被报道与核糖体RNA和核糖体合成相互作用。与这些发现一致，DNMT 1和MBD 2以及p66α在ND神经元中表现出与核糖体标记物RPL 26和5.8s rRNA共定位的点状细胞质免疫反应性。相比之下，AD神经元普遍缺乏这种染色，RPL 26和5.8s rRNA免疫反应性有质的下降。总的来说，这些发现表明AD易感神经元的表观遗传功能障碍。
DNA methylation is a vital component of the epigenetic machinery that orchestrates changes in multiple genes and helps regulate gene expression in all known vertebrates. We evaluated immunoreactivity for two markers of DNA methylation and eight methylation maintenance factors in entorhinal cortex layer II, a region exhibiting substantial Alzheimer's disease (AD) pathology in which expression changes have been reported for a wide variety of genes. We show, for the first time, neuronal immunoreactivity for all 10 of the epigenetic markers and factors, with highly significant decrements in AD cases. These decrements were particularly marked in PHF1/PS396 immunoreactive, neurofibrillary tangle-bearing neurons. In addition, two of the DNA methylation maintenance factors, DNMT1 and MBD2, have been reported also to interact with ribosomal RNAs and ribosome synthesis. Consistent with these findings, DNMT1 and MBD2, as well as p66α, exhibited punctate cytoplasmic immunoreactivity that co-localized with the ribosome markers RPL26 and 5.8s rRNA in ND neurons. By contrast, AD neurons generally lacked such staining, and there was a qualitative decrease in RPL26 and 5.8s rRNA immunoreactivity. Collectively, these findings suggest epigenetic dysfunction in AD-vulnerable neurons.
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