King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Anatomy, King Abdulaziz University Medical College, King Abdulaziz University, Jeddah, Saudi Arabia.
CNS Neurol Disord Drug Targets. 2017;16(9):1027-1038. doi: 10.2174/1871527316666171023153837.
BACKGROUND & OBJECTIVE: Involvement of amyloid beta and tau proteins in pathogenesis of Alzheimer's disease (AD) has been studied extensively. However, electrophysiological activity, and cellular processes like membrane transport are mostly unstudied. Electrophysiological processes provide a bridge between brain activity and cognition, and show promise as translatable biomarkers in preclinical and clinical applications. Biochemical imbalance leads to change in glutamate-based neurotransmission, antioxidant capacity, and in membrane polarization-repolarization events, eventually, resulting in AD. We hypothesize that in AD, these processes are unified at a single metabolic hub and we carried out a holistic system-biology approach.
In the present study, we integrated and analyzed multiple AD expression datasets from the GEO database to identify significant genes associated with electrophysiological pathways and attempted determination of interconnected canonical molecular pathways. Partek Genomic suite based expression analysis identified 200 significantly expressed genes using cut-off value of ≤ 0.05 and 2 fold change. Transducer of ERBB2, 2 (TOB2); lactotransferrin (LFT) and RAS-like, family 12 (RASL12) were most up-regulated genes, while neurofilament light polypeptide (NEFL); collagen, type V, alpha 2 (COL5A2); visinin-like 1 (VSNL1); cannabinoid receptor 1 (brain) (CNR1); neurofilament, medium polypeptide (NEFM); regulator of G-protein signaling 4 (RGS4), and synaptosomalassociated protein, 25kDa (SNAP25) were most down-regulated ones.
Interestingly, we found majority of transporter genes identified in dataset as downregulated. Ingenuity pathways analysis revealed glutamate receptor signaling, CREB signaling, dopamine- DARPP32 feedback in cAMP signaling, fMLP signaling in neutrophils, and synaptic long term potentiation pathway playing critical role in AD pathophysiology and having correlation with electrophysiological dysfunction.
淀粉样β蛋白和tau 蛋白在阿尔茨海默病（AD）发病机制中的作用已得到广泛研究。然而，电生理活性和细胞过程（如膜转运）大多未被研究。电生理过程在大脑活动和认知之间架起了桥梁，并作为临床前和临床应用中的转化生物标志物具有很大的潜力。生化失衡导致基于谷氨酸的神经递质传递、抗氧化能力以及膜去极化-再极化事件改变，最终导致 AD。我们假设在 AD 中，这些过程在单个代谢枢纽上统一起来，我们进行了整体系统生物学方法。
在本研究中，我们整合和分析了 GEO 数据库中的多个 AD 表达数据集，以确定与电生理途径相关的显著基因，并尝试确定相互关联的经典分子途径。Partek 基因组套件基于表达分析使用≤0.05 和 2 倍变化的截止值确定了 200 个显著表达的基因。跨膜 ERBB2 二聚体转录物 2（TOB2）；乳转铁蛋白（LFT）和 RAS 样家族 12（RASL12）是上调最显著的基因，而神经丝轻多肽（NEFL）；胶原，类型 V，α 2（COL5A2）；类视黄醇蛋白 1（VSNL1）；大麻素受体 1（脑）（CNR1）；神经丝，中等多肽（NEFM）；G 蛋白信号转导调节因子 4（RGS4）和突触相关蛋白 25kDa（SNAP25）是下调最显著的基因。
有趣的是，我们发现数据集中大多数鉴定的转运体基因被下调。Ingenuity 通路分析表明，谷氨酸受体信号、CREB 信号、多巴胺-DARPP32 在 cAMP 信号中的反馈、中性粒细胞中的 fMLP 信号以及突触长时程增强途径在 AD 病理生理学中发挥关键作用，并与电生理功能障碍相关。
