School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, P. R. China and College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, P. R. China.
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, P. R. China.
Brief Bioinform. 2019 Mar 25;20(2):598-608. doi: 10.1093/bib/bby021.
Increasing evidence has revealed the multiple roles of long noncoding RNAs (lncRNAs) in neurodevelopment, brain function and aging, and their dysregulation was implicated in many types of neurological diseases. However, expression pattern and diagnostic role of lncRNAs in Alzheimer's disease (AD) remain largely unknown and has gained significant attention. In this study, we performed a comparative analysis for lncRNA expression profiles in four brain regions in brain aging and AD. Our analysis revealed age- and disease-dependent region-specific lncRNA expression patterns in aging and AD. Moreover, we identified a panel of nine lncRNAs (termed LncSigAD9) in a discovery cohort of 114 samples using supervised machine learning and stepwise selection method. The LncSigAD9 was able to differentiate between AD and healthy controls with high diagnostic sensitivity and specificity both in the discovery cohort (86.3 and 89.5%) and the additional independent AD cohort (90.8 and 83.8%). The receiver operating characteristic curves for the LncSigAD9 were 0.863 and 0.939 for discovery and independent cohorts, respectively. Furthermore, the LncSigAD9 demonstrated higher diagnostic performance than nine-minus-one lncRNA signature and mRNA-based signature with a similar number of genes. In silico functional analysis indicated the involvement of lncRNA expression variation in brain development- and metabolism-related biological processes. Taken together, our study highlights the importance of lncRNAs in brain aging and AD, and demonstrated the utility of lncRNAs as a promising biomarker for early AD diagnosis and treatment.
越来越多的证据表明，长非编码 RNA（lncRNA）在神经发育、大脑功能和衰老中具有多种作用，其失调与许多类型的神经退行性疾病有关。然而，lncRNA 在阿尔茨海默病（AD）中的表达模式和诊断作用在很大程度上仍然未知，并引起了广泛关注。在这项研究中，我们对四个脑区在脑老化和 AD 中的 lncRNA 表达谱进行了比较分析。我们的分析揭示了衰老和 AD 中与年龄和疾病相关的区域特异性 lncRNA 表达模式。此外，我们使用有监督的机器学习和逐步选择方法，在一个包含 114 个样本的发现队列中确定了一组 9 个 lncRNA（称为 LncSigAD9）。LncSigAD9 能够在发现队列（86.3%和 89.5%）和额外的独立 AD 队列（90.8%和 83.8%）中区分 AD 和健康对照组，具有较高的诊断敏感性和特异性。LncSigAD9 的受试者工作特征曲线在发现队列和独立队列中的曲线下面积分别为 0.863 和 0.939。此外，LncSigAD9 的诊断性能高于具有相似基因数量的 9 个减去 1 个 lncRNA 特征和基于 mRNA 的特征。计算功能分析表明，lncRNA 表达变化参与了与大脑发育和代谢相关的生物学过程。总之，我们的研究强调了 lncRNA 在大脑老化和 AD 中的重要性，并证明了 lncRNA 作为早期 AD 诊断和治疗有前途的生物标志物的应用。
