阿尔茨海默病中的微小RNA:诊断标志物还是治疗药物?

MicroRNAs in Alzheimer's Disease: Diagnostic Markers or Therapeutic Agents?

作者信息

Angelucci Francesco, Cechova Katerina, Valis Martin, Kuca Kamil, Zhang Bing, Hort Jakub

机构信息

Memory Clinic, Department of Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.

International Clinical Research Centre, St. Anne's University Hospital, Brno, Czechia.

出版信息

Front Pharmacol. 2019 Jun 18;10:665. doi: 10.3389/fphar.2019.00665. eCollection 2019.

Abstract

MicroRNAs (miRNAs) are small non-coding nucleic acids able to post-transcriptionally regulate gene expression by binding to complementary sequences of target messenger RNA (mRNA). It has been estimated that at least 1% of the human genome encodes miRNA and every miRNA can regulate up to 200 mRNAs. These findings suggest that dysregulation of miRNA expression could be associated with several human pathological conditions including central neurological disorders. Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the elderly. The characteristic symptoms are a progressive loss of memory and other cognitive functions due to the impairment of particular types of neurons and synapses, leading to neuronal death. At present, the available symptomatic treatments can only slow down disease progression without stopping it. miRNAs are widely found within the nervous system where they are key regulators of functions such as neurite outgrowth, dendritic spine morphology, neuronal differentiation, and synaptic plasticity. This has been the clue for considering miRNAs crucial molecules to be studied in AD, and nowadays, dysfunction of miRNAs in AD is increasingly recognized. In this review, we summarized existing evidence about miRNAs as biomarkers or therapeutic agents. The field of miRNAs as biomarkers is more advanced in terms of human data, and it is likely that miRNAs will be used successfully in the near future. Given the huge number of miRNAs potentially involved in diagnostics, miRNA panels will be used for specific tasks such as the stage of the disease, the risk prediction, and disease progression. The field of miRNAs as therapeutics is rapidly developing, and it offers a huge variety of solutions. These include positive effects related to beta-amyloid or tau reduction, increased number of neurons, inhibition of apoptosis, protection of synapses, transformation of other cellular elements into missing/deficient neurons in AD, and so on. It is predictable that both areas of research will be carried forward. However, given the absence of an AD therapy able to stop or reverse the disease, it is desirable to accelerate research on miRNAs as therapeutic agents.

摘要

微小RNA(miRNA)是一类小型非编码核酸,能够通过与靶信使核糖核酸(mRNA)的互补序列结合,在转录后水平调控基因表达。据估计,人类基因组中至少1%的基因编码miRNA,且每个miRNA可调控多达200种mRNA。这些发现表明,miRNA表达失调可能与包括中枢神经系统疾病在内的多种人类病理状况相关。阿尔茨海默病(AD)是一种神经退行性疾病,也是老年人痴呆最常见的病因。其特征性症状是由于特定类型的神经元和突触受损导致记忆及其他认知功能逐渐丧失,进而导致神经元死亡。目前,现有的对症治疗只能减缓疾病进展,无法阻止病情发展。miRNA广泛存在于神经系统中,是神经突生长、树突棘形态、神经元分化和突触可塑性等功能的关键调节因子。这成为了将miRNA视为AD研究关键分子的线索,如今,AD中miRNA功能失调越来越受到认可。在本综述中,我们总结了关于miRNA作为生物标志物或治疗剂的现有证据。就人类数据而言,miRNA作为生物标志物的领域更为先进,miRNA很可能在不久的将来成功应用。鉴于可能参与诊断的miRNA数量众多,miRNA组合将用于特定任务,如疾病分期、风险预测和疾病进展。miRNA作为治疗剂的领域正在迅速发展,并提供了多种多样的解决方案。这些包括与β-淀粉样蛋白或tau蛋白减少、神经元数量增加、细胞凋亡抑制、突触保护、将AD中其他细胞成分转化为缺失/缺陷神经元等相关的积极作用。可以预见,这两个研究领域都将向前推进。然而,鉴于目前尚无能够阻止或逆转AD疾病的疗法,加速对miRNA作为治疗剂的研究是很有必要的。

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