Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Neuroscience. 2012 Sep 18;220:256-66. doi: 10.1016/j.neuroscience.2012.06.029. Epub 2012 Jun 21.
In Alzheimer's disease (AD) the complex interplay between environment and genetics has hampered the identification of effective therapeutics. However, epigenetic mechanisms could underlie this complexity. Here, we explored the potential role of epigenetic alterations in AD by investigating gene expression levels and chromatin remodeling in selected AD-related genes. Analysis was performed in the brain of the triple transgenic animal model of AD (3xTg-AD) and in peripheral blood mononuclear cells (PBMCs) from patients diagnosed with AD or Mild Cognitive Impairment (MCI). BACE1 mRNA levels were increased in aged 3xTg-AD mice as well as in AD PBMCs along with an increase in promoter accessibility and histone H3 acetylation, while the BACE1 promoter region was less accessible in PBMCs from MCI individuals. Ncstn was downregulated in aged 3xTg-AD brains with a condensation of chromatin and Sirt1 mRNA levels were decreased in these animals despite alterations in histone H3 acetylation. Neither gene was altered in AD PBMCs. The ADORA2A gene was not altered in patients or in the 3xTg-AD mice. Overall, our results suggest that chromatin remodeling plays a role in mRNA alterations in AD, prompting for broader and more detailed studies of chromatin and other epigenetic alterations and their potential use as biomarkers in AD.
在阿尔茨海默病（AD）中，环境和遗传之间的复杂相互作用阻碍了有效治疗方法的确定。然而，表观遗传机制可能是这种复杂性的基础。在这里，我们通过研究选定的与 AD 相关基因的基因表达水平和染色质重塑，探讨了表观遗传改变在 AD 中的潜在作用。分析在 AD 的三转基因动物模型（3xTg-AD）的大脑和 AD 或轻度认知障碍（MCI）患者的外周血单核细胞（PBMC）中进行。BACE1 mRNA 水平在年龄较大的 3xTg-AD 小鼠以及 AD PBMC 中增加，同时启动子可及性和组蛋白 H3 乙酰化增加，而 MCI 个体的 PBMC 中 BACE1 启动子区域的可及性较低。Ncstn 在年龄较大的 3xTg-AD 大脑中下调，染色质浓缩，尽管组蛋白 H3 乙酰化发生改变，但这些动物中的 Sirt1 mRNA 水平下降。这两个基因在 AD PBMC 中均未改变。ADORA2A 基因在患者或 3xTg-AD 小鼠中均未改变。总体而言，我们的研究结果表明，染色质重塑在 AD 中的 mRNA 改变中发挥作用，这促使我们更广泛和更详细地研究染色质和其他表观遗传改变及其在 AD 中的潜在作为生物标志物的用途。
