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Influence of N6-methyladenosine (M6a) Modification on Cell Phenotype in Alzheimer’s Disease

Pengyun Ni ,Kaiting Pan ,Bingbing Zhao

Abstract

Recent research has suggested that m6A modification takes on critical significance to Neurodegeneration. As indicated by the genome-wide map of m6A mRNA, genes in Alzheimer’s disease model achieved significant m6A methylation. This study aimed to investigate the hub gene and pathway of m6A modification in the pathogenesis of AD. Moreover, possible brain regions with higher gene expression levels and compounds exerting potential therapeutic effects were identified. Thus, this study can provide a novel idea to explore the treatment of AD.

Introduction

Alzheimer’s disease (AD) has been confirmed as one of the most common Neurodegeneration, characterized by a progressive decline in memory function and even cognitive impairment [1]. AD has a high incidence in the elderly population and in some countries [2]. Besides, AD is recognized as a problem that should arouse the attention of the society and the government. Due to the lack of effective treatment, AD patients and their families are currently subjected to considerable number of inconvenience and health risks. The pathogenesis and therapy of AD should be urgently studied.

Materials and method

Two microarray datasets (GSE5281 and GSE48350) were downloaded in this study from the Gene Expression Omnibus (GEO) database [23] (http://www.ncbi.nlm.nih.gov/gds/) investigating gene expression profiles changes in patients with Alzheimer’s disease.

The gene expression profile GSE5281 and GSE48350 were generated on the platform of GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array. This dataset comprises 247 control samples and 167 AD samples.

Results

The differential gene expression analysis between samples was performed to compare the difference in gene expression between the AD group and the control group. The gene dataset GSE5281 and GSE48350 contained a total of 167 Alzheimer’s disease samples and 247 normal samples. With the Limma package for differential expression analysis, with |log2(Fold Change)| > 0.58 and P.value < 0.05 as the screening conditions, 917 differently expressed genes in brain tissues of AD patients were identified, as compared with normal brain tissues. To be specific, 265 were up-regulated, and 652 were down-regulated, and the clustering analysis of the above-described differential genes was conducted, with the result illustrated in the volcano plot (Fig 1A). Fig 1B presents a heat map of data set, suggesting that the clustering of samples is highly reliable.

Discussion

Alzheimer’s disease refers to a neurodegenerative disorder that generally results in memory impairment and cognitive impairment [33]. Most existing research has reported that the pathological changes of AD arise from the accumulation of amyloid β plaques in the brain, mainly in the form of inflammation and tau protein aggregation in neurofibrillary tangles [34]. Several studies have demonstrated that m6A gene mutation and high level of gene expression show a correlation with the occurrence and development of AD [21, 22]. However, the mechanism of action remains unclear and should be studied in depth

Conclusions

In general, the potential role of m6A modification in Alzheimer’s disease was investigated. The relevant hub genes (e.g., SOX2, KLF4, ITGB4, CD44, MSX1, YAP1, AQP1, EGR2, YWHAZ, and TFAP2C) and the involved pathways were identified through the bioinformatics analysis. The biological changes may be correlated with retinoic acid, DNA damage response, and cysteine-type endopeptidase activity, which may occur via the Hippo signaling pathway. Furthermore, the brain regions with high expression of hub gene were identified, and the compounds exerting potential therapeutic effects on AD were predicted. On that basis, this study can lay a theoretical basis for exploring novel therapies for AD.

Acknowledgments

The authors gratefully acknowledge the data provided by patients and researchers participating in GEO.

Citation: Ni P, Pan K, Zhao B (2023) Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer’s disease. PLoS ONE 18(8): e0289068. https://doi.org/10.1371/journal.pone.0289068

Editor: Divakar Sharma, Lady Hardinge Medical College, INDIA

Received: November 21, 2022; Accepted: July 11, 2023; Published: August 7, 2023

Copyright: © 2023 Ni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All Expressions of GSE5281 and GSE48350, gene of m6A datas are available from the Figshare database. (DOI: 10.6084/m9.figshare.22656136, URL: https://figshare.com/account/home).

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0289068#ack

 

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