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. 2021 Nov 25:13:742242.
doi: 10.3389/fnagi.2021.742242. eCollection 2021.

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer's Disease: A Systematic Scoping Review

Hani Sabaie  1   2 , Nazanin Amirinejad  3 , Mohammad Reza Asadi  2 , Abbas Jalaiei  2 , Yousef Daneshmandpour  2 , Omidvar Rezaei  4 , Mohammad Taheri  4   5 , Maryam Rezazadeh  1   2
Affiliations

Molecular Insight Into the Therapeutic Potential of Long Non-coding RNA-Associated Competing Endogenous RNA Axes in Alzheimer's Disease: A Systematic Scoping Review

Hani Sabaie et al. Front Aging Neurosci. .

Abstract

Alzheimer's disease (AD) is a heterogeneous degenerative brain disorder with a rising prevalence worldwide. The two hallmarks that characterize the AD pathophysiology are amyloid plaques, generated via aggregated amyloid β, and neurofibrillary tangle, generated via accumulated phosphorylated tau. At the post-transcriptional and transcriptional levels, the regulatory functions of non-coding RNAs, in particular long non-coding RNAs (lncRNAs), have been ascertained in gene expressions. It is noteworthy that a number of lncRNAs feature a prevalent role in their potential of regulating gene expression through modulation of microRNAs via a process called the mechanism of competing endogenous RNA (ceRNA). Given the multifactorial nature of ceRNA interaction networks, they might be advantageous in complex disorders (e.g., AD) investigations at the therapeutic targets level. We carried out scoping review in this research to analyze validated loops of ceRNA in AD and focus on ceRNA axes associated with lncRNA. This scoping review was performed according to a six-stage methodology structure and PRISMA guideline. A systematic search of seven databases was conducted to find eligible articles prior to July 2021. Two reviewers independently performed publications screening and data extraction, and quantitative and qualitative analyses were conducted. Fourteen articles were identified that fulfill the inclusion criteria. Studies with different designs reported nine lncRNAs that were experimentally validated to act as ceRNA in AD in human-related studies, including BACE1-AS, SNHG1, RPPH1, NEAT1, LINC00094, SOX21-AS1, LINC00507, MAGI2-AS3, and LINC01311. The BACE1-AS/BACE1 was the most frequent ceRNA pair. Among miRNAs, miR-107 played a key role by regulating three different loops. Understanding the various aspects of this regulatory mechanism can help elucidate the unknown etiology of AD and provide new molecular targets for use in therapeutic and clinical applications.

Keywords: Alzheimer’s disease; antisense oligonucleotides; competing endogenous RNA; long non-coding RNA; miRNA sponge.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Competing endogenous RNA (ceRNA) model. All transcriptome components, such as long non-coding RNAs (lncRNAs), circRNAs, pseudogenes, and mRNAs that share common MRE, can function as ceRNAs and can co-regulate each other by sponging shared miRNAs. Differentially expressed transcripts can lead to ceRNA dysregulation and biological alterations. ceRNA. (A) Down-regulation of ceRNAs increases the amounts of free miRNAs, thereby repressing target expression. (B) Conversely, up-regulation of ceRNAs reduces free miRNAs abundance, thereby derepressing target expression. Competing endogenous RNA; circRNA, circular RNA; lncRNA, long non-coding RNA; miRNA, microRNA; MRE, miRNA response element.
FIGURE 2
FIGURE 2
Search strategyflow chart based on the PRISMA flow diagram.
FIGURE 3
FIGURE 3
Validated lncRNA-associated ceRNA axes in Alzheimer’s disease. The loops were visualized using Cytoscape v3.8.0 software (Shannon et al., 2003) based on lncRNA-miRNA-mRNA interactions. Red represents the damaging role, and blue represents the protective role of competing endogenous RNA axes. LncRNAs, miRNAs, and mRNAs are represented by hexagon, round rectangle, and ellipse, respectively. LncRNA, long non-coding RNA; miRNA, microRNA.
FIGURE 4
FIGURE 4
miR-107 regulates different competing endogenous RNA (ceRNA) loops. Loop A (NEAT1 and targets of miR-107), loop B (SOX21-AS1 and targets of miR-107), and loop C (BACE1-AS and BACE1) were all regulated by miR-107. Red represents the damaging role of ceRNA axes. Lon non-coding RNAs, microRNAs, and mRNAs are represented by hexagon, round rectangle, and ellipse, respectively.
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