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Abnormality of m6A mRNA Methylation Is Involved in Alzheimer’s Disease

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Han, Min, Liu, Zhen, Xu, Yingying, Liu, Xiangtian, Wang, Dewei, Li, Fan, Wang, Yun, Bi, Jianzhong·2020·Frontiers in Neuroscience
DOI 10.3389/fnins.2020.00098PMC PMC7058666
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Abstract

Alzheimer's disease (AD), the most common form of dementia, is highly prevalent in older adults. The main clinical feature is the progressive decline of memory function, which eventually leads to the decline of cognitive function. At present, the pathogenesis of AD is unclear. In the disease process, synaptic changes are the key. Recent studies have shown that the dysregulation of RNA methylation is related to many biological processes, including neurodevelopment and neurodegenerative diseases. N6-methyladenosine (m6A) is the most abundant modification in eukaryotic RNA. In this study, RNA m6A methylation was quantified in APP/PS1 transgenic mice, which is an AD mouse model, and C57BL/6 control mice, and data showed that m6A methylation was elevated in the cortex and the hippocampus of APP/PS1 transgenic mice. Next, the alterations of m6A RNA methylation in AD and in C57BL/6 mice were investigated using high-throughput sequencing. Genome-wide maps of m6A mRNA showed that the degrees of m6A methylation were higher in many genes and lower in others in AD mice. Interestingly, the expression of the m6A methyltransferase METTL3 was elevated and that of the m6A demethylase FTO was decreased in AD mice. The data were analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, and pathways that might be related to synaptic or neuron development and growth were constructed. The related pathways and genes predicted the potential roles of the differentially expressed m6A methylation RNA in AD. Collectively, our findings demonstrate that the m6A methylation of RNA promotes the development of AD.

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FIGURE 1 Comparison of methylation content of the cortex, hippocampus, and cerebellum samples between the two groups. Among them, m6A RNA methylation significantly increased in the hippocampus and cortex samples. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, *P < 0.05.
FIGURE 1 Comparison of methylation content of the cortex, hippocampus, and cerebellum samples between the two groups. Among them, m6A RNA methylation significantly increased in the hippocampus and cortex samples. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, *P < 0.05.CC BY · PubMed Central
FIGURE 2 Gene ontology analysis showing that m6A RNA methylation is related to specific functional roles in AD. The analyzed genes with increased m6A RNA methylation expression in the AD group are shown; biological process-specific function (A,B), cell component-specific function (C,D), and molecular function-specific function (E,F).
FIGURE 2 Gene ontology analysis showing that m6A RNA methylation is related to specific functional roles in AD. The analyzed genes with increased m6A RNA methylation expression in the AD group are shown; biological process-specific function (A,B), cell component-specific function (C,D), and molecular function-specific function (E,F).CC BY · PubMed Central
FIGURE 3 Kyoto Encyclopedia of Genes and Genomes pathway analysis of genes with differentially expressed m6A RNA methylation, showing the top 18 enrichment scores. Analysis predicted the pathways affected by the variation of mRNAs in AD brain samples; biological processes (A), cell components (B), and molecular functions (C) show their own pathways. The enrichment score was calculated as –log10 (P-value).
FIGURE 3 Kyoto Encyclopedia of Genes and Genomes pathway analysis of genes with differentially expressed m6A RNA methylation, showing the top 18 enrichment scores. Analysis predicted the pathways affected by the variation of mRNAs in AD brain samples; biological processes (A), cell components (B), and molecular functions (C) show their own pathways. The enrichment score was calculated as –log10 (P-value).CC BY · PubMed Central
FIGURE 4 Pathways associated with synaptic function, from which genes to be studied were selected. Glutamatergic synapse (A), axon guidance (B), long-term potentiation (C), and calcium signaling pathway (D).
FIGURE 4 Pathways associated with synaptic function, from which genes to be studied were selected. Glutamatergic synapse (A), axon guidance (B), long-term potentiation (C), and calcium signaling pathway (D).CC BY · PubMed Central
FIGURE 5 The expression of METTL3 gene is increased and that of FTO gene is decreased in the AD group. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 5 per group, *P < 0.05, **P < 0.01.
FIGURE 5 The expression of METTL3 gene is increased and that of FTO gene is decreased in the AD group. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 5 per group, *P < 0.05, **P < 0.01.CC BY · PubMed Central
FIGURE 6 AD group transplantation versus the control group. Expression of METTL3 and FTO enzymes in the brains of AD mice is different from that in the control group. The relative densities of all proteins bands are normalized to β-actin. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, *P < 0.05.
FIGURE 6 AD group transplantation versus the control group. Expression of METTL3 and FTO enzymes in the brains of AD mice is different from that in the control group. The relative densities of all proteins bands are normalized to β-actin. Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, *P < 0.05.CC BY · PubMed Central
FIGURE 7 AD animal model validation results. (A) The expression level of Aβ in APP/PS1 mice is significantly increased compared with that of the control group, while synaptophysin is decreased in AD animal models (B). Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, **P < 0.01.
FIGURE 7 AD animal model validation results. (A) The expression level of Aβ in APP/PS1 mice is significantly increased compared with that of the control group, while synaptophysin is decreased in AD animal models (B). Student’s t-test was used to detect differences between the two groups, and data are presented as mean ± SEM; n = 6 per group, **P < 0.01.CC BY · PubMed Central
FIGURE 8 (A) High-throughput sequencing analysis shows statistically significant differences in m6A RNA methylation of AMPA, NMDA, and SEMA in the hippocampus of the two groups of mice; n = 3 per group, ***P < 0.001. (B) The mRNA levels of AMPA and NMDA in the brains of AD mice were reduced by quantitative RT-PCR, and that of SEMA is the opposite. β-actin was measured as the reference gene; n = 5 per group. Student’s t-test was used to detect differences between the two groups; data are presented as mean ± SEM; *P < 0.05.
FIGURE 8 (A) High-throughput sequencing analysis shows statistically significant differences in m6A RNA methylation of AMPA, NMDA, and SEMA in the hippocampus of the two groups of mice; n = 3 per group, ***P < 0.001. (B) The mRNA levels of AMPA and NMDA in the brains of AD mice were reduced by quantitative RT-PCR, and that of SEMA is the opposite. β-actin was measured as the reference gene; n = 5 per group. Student’s t-test was used to detect differences between the two groups; data are presented as mean ± SEM; *P < 0.05.CC BY · PubMed Central

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Metadata

Authors
Han, M., Liu, Z., Xu, Y., Liu, X., Wang, D., Li, F., Wang, Y., & Bi, J.
Affiliations
  • Second Hospital of Shandong University (CN)
  • Shandong University (CN)
Corresponding author
Wang, Yun
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2020-02-28
Volume
14
Pages
98-98
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2020.00098
PMC
PMC7058666
OpenAlex
W3008232393
Cited by
286
References
29
Citations by year
2026: 26 · 2025: 25 · 2024: 43 · 2023: 64 · 2022: 52 · 2021: 62 · 2020: 14
FWCI
16.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Keywords
Alzheimer's disease, N6-methyladenosine, RNA methylation, APP/PS1 mice, synaptic dysfunction, hippocampus, cortex, neurodegeneration

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