Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China.
Mol Med Rep. 2018 Aug;18(2):2164-2170. doi: 10.3892/mmr.2018.9190. Epub 2018 Jun 19.
Alzheimer's disease (AD) is the most common type of neurological disorder that results from brain cell death; however, not all brain regions are simultaneously affected to the same extent. Despite single biomarkers for AD having been determined on a genome‑wide scale, the differential co‑expression in gene pairs between regions and interactions with other types of cellular molecules, particularly non‑coding (nc)RNAs, are often overlooked in studies investigating the underlying mechanisms associated with AD. In the present study, based on 1,548 samples obtained from a cohort of 90 patients with AD spanning 19 brain regions, a gene‑pair based method was established for the classification of 19 brain regions into seven different groups, including marked disparate groupings of six single regions and a cluster of another 13 regions as revealed by principal component analysis (PCA). To further investigate the different underlying mechanisms associated with each group, five highly interconnected functional modules of the protein‑protein interaction network were demonstrated to characterize the seven region groups containing six single groups and 13 clustered regions based on 4,731 gene‑pairs. Genes in two of the functional modules exhibited a strong association with pathways associated with the nervous system, including cholinergic synapses, circadian entrainment and dopaminergic synapses. Notably, following integration of these two modules with a ncRNA‑mediated network, one module demonstrated a strong association with micro (mi)RNAs, which were revealed to interact with numerous long non‑coding (lnc)RNAs associated with AD, such as metastasis associated lung adenocarcinoma transcript 1 and taurine upregulated 1. This suggested that mRNAs and lncRNAs may represent competing endogenous RNAs for binding with miRNAs. Thus, these results indicated that the ncRNA‑mediated gene regulatory module detected by the established gene pair‑based method may further the understanding of underlying mechanisms associated with AD as well as aid the development of novel therapeutic strategies for the treatment of patients with AD.
阿尔茨海默病（AD）是最常见的神经退行性疾病，源于脑细胞死亡；然而，并非所有脑区都同时受到同等程度的影响。尽管已经在全基因组范围内确定了 AD 的单一生物标志物，但在研究与 AD 相关的潜在机制时，往往会忽略区域间基因对的差异共表达以及与其他类型细胞分子（尤其是非编码（nc）RNAs）的相互作用。在本研究中，基于从跨越 19 个脑区的 90 名 AD 患者的队列中获得的 1548 个样本，建立了一种基于基因对的方法，可将 19 个脑区划分为七个不同的组，包括通过主成分分析（PCA）揭示的六个单区域的明显不同分组和另 13 个区域的聚类。为了进一步研究与每个组相关的不同潜在机制，基于 4731 个基因对，展示了五个高度相互关联的蛋白质-蛋白质相互作用网络功能模块，以描绘包含六个单组和 13 个聚类区域的七个区域组。两个功能模块中的基因与包括胆碱能突触、昼夜节律和多巴胺能突触在内的与神经系统相关的途径表现出强烈的关联。值得注意的是，在将这两个模块与 ncRNA 介导的网络集成后，一个模块与 micro（mi）RNAs 强烈相关，miRNAs 与许多与 AD 相关的长非编码（lnc）RNAs 相互作用，例如转移相关肺腺癌转录物 1 和牛磺酸上调 1。这表明 mRNAs 和 lncRNAs 可能代表与 miRNAs 结合的竞争性内源 RNA。因此，这些结果表明，基于建立的基因对方法检测到的 ncRNA 介导的基因调控模块可能有助于深入了解与 AD 相关的潜在机制，并为 AD 患者的治疗开发新的治疗策略提供帮助。
