Login Register Cart 0
Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

RNA Hypomethylation and Unchanged DNA Methylation Levels in the Cortex of ApoE4 Carriers and Alzheimer’s Disease Subjects

Author(s): Wei-Bin Shen, James Jiao Yang and Peixin Yang*

Volume 19, Issue 7, 2022

Published on: 22 September, 2022

Page: [530 - 540] Pages: 11

DOI: 10.2174/1567205019666220831125142

Price: $65

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and ApoE4 variants are significant risk factors for AD. Epigenetic modifications are involved in AD pathology. However, it is unclear whether DNA/RNA methylation plays a role in AD pathology, and dysregulation of DNA/RNA methylation occurs in ApoE4 carriers.

Objective: The present study aimed to determine whether dysregulation of DNA/RNA methylation is present in the brains of ApoE4 carriers and AD patients.

Methods: In this study, postmortem brain tissues from carriers of ApoE4 and ApoE3, from AD and non- AD controls, were used in the analysis of DNA/RNA methylation, methyltransferases, and their demethylases.

Results: Immunofluorescence staining indicates that RNA methylation is suppressed in ApoE4 carriers. Further analysis shows that the expression of RNA methyltransferases and an RNA methylation reader is suppressed in ApoE4 carriers, whereas RNA demethylase expression is increased. RNA hypomethylation occurs in NeuN+ neurons in ApoE4 carriers and AD patients. Furthermore, in ApoE4 carriers, both DNA methyltransferases and demethylases are downregulated, and overall DNA methylation levels are unchanged.

Conclusion: Our finding indicates that RNA methylation decreased in ApoE4 carriers before AD pathology and AD individuals. The expression of RNA methyltransferases and RNA methylation reader is inhibited, and RNA demethylase is upregulated in ApoE4 carriers, which leads to suppression of RNA methylation, and the suppression precedes the AD pathogenesis and persists through AD pathology.

Keywords: ApoE4, methyltransferases, demethylase, DNA methylation, RNA methylation, Alzheimer’s disease.

« Previous Next »
[1]
Association As. Alzheimer's Facts and Figures Report. 2018. Available from: https://wwwalzorg/media/HomeOffice/Facts%20 and%20Figures/facts-and-figurespdf2018
[2]
Sherrington R, Rogaev EI, Liang Y, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375(6534): 754-60.
[http://dx.doi.org/10.1038/375754a0] [PMID: 7596406]
[3]
Citron M, Westaway D, Xia W, et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nat Med 1997; 3(1): 67-72.
[http://dx.doi.org/10.1038/nm0197-67] [PMID: 8986743]
[4]
Li P, Marshall L, Oh G, et al. Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms. Nat Commun 2019; 10(1): 2246.
[http://dx.doi.org/10.1038/s41467-019-10101-7] [PMID: 31113950]
[5]
Wei X, Zhang L, Zeng Y. DNA methylation in Alzheimer’s disease: In brain and peripheral blood. Mech Ageing Dev 2020; 191: 111319.
[http://dx.doi.org/10.1016/j.mad.2020.111319] [PMID: 32721406]
[6]
Poon CH, Tse LSR, Lim LW. DNA methylation in the pathology of Alzheimer’s disease: From gene to cognition. Ann N Y Acad Sci 2020; 1475(1): 15-33.
[http://dx.doi.org/10.1111/nyas.14373] [PMID: 32491215]
[7]
Prasad GR, Jho E. A concise review of human brain methylome during aging and neurodegenerative diseases. BMB Rep 2019; 52(10): 577-88.
[http://dx.doi.org/10.5483/BMBRep.2019.52.10.215] [PMID: 31462381]
[8]
Dick KJ, Nelson CP, Tsaprouni L, et al. DNA methylation and body-mass index: A genome-wide analysis. Lancet 2014; 383(9933): 1990-8.
[http://dx.doi.org/10.1016/S0140-6736(13)62674-4] [PMID: 24630777]
[9]
Wei CM, Gershowitz A, Moss BERNARD. N6, O2′-dimethyladenosine a novel methylated ribonucleoside next to the 5′ terminal of animal cell and virus mRNAs. Nature 1975; 257(5523): 251-3.
[http://dx.doi.org/10.1038/257251a0] [PMID: 1161029]
[10]
Yang C, Hu Y, Zhou B, et al. The role of m6A modification in physiology and disease. Cell Death Dis 2020; 11(11): 960.
[http://dx.doi.org/10.1038/s41419-020-03143-z] [PMID: 33162550]
[11]
Li L, Zang L, Zhang F, et al. Fat mass and obesity-associated (FTO) protein regulates adult neurogenesis. Hum Mol Genet 2017; 26(13): 2398-411.
[http://dx.doi.org/10.1093/hmg/ddx128] [PMID: 28398475]
[12]
Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 2012; 149(7): 1635-46.
[http://dx.doi.org/10.1016/j.cell.2012.05.003] [PMID: 22608085]
[13]
Han M, Liu Z, Xu Y, et al. Abnormality of m6A mRNA methylation is involved in Alzheimer’s disease. Front Neurosci 2020; 14: 98.
[http://dx.doi.org/10.3389/fnins.2020.00098] [PMID: 32184705]
[14]
Widagdo J, Zhao QY, Kempen MJ, et al. Experience-dependent accumulation of N6 -methyladenosine in the prefrontal cortex is associated with memory processes in mice. J Neurosci 2016; 36(25): 6771-7.
[http://dx.doi.org/10.1523/JNEUROSCI.4053-15.2016] [PMID: 27335407]
[15]
Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD. Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2009; 106(34): 14670-5.
[http://dx.doi.org/10.1073/pnas.0903563106] [PMID: 19667196]
[16]
Lachen-Montes M, Gonzalez-Morales A, Morentin XM, et al. An early dysregulation of FAK and MEK/ERK signaling pathways precedes the β-amyloid deposition in the olfactory bulb of APP/PS1 mouse model of Alzheimer’s disease. J Proteomics 2016; 148: 149-58.
[http://dx.doi.org/10.1016/j.jprot.2016.07.032] [PMID: 27498392]
[17]
Husain MA, Laurent B, Plourde M. APOE and Alzheimer’s disease: From lipid transport to physiopathology and therapeutics. Front Neurosci 2021; 15: 630502.
[http://dx.doi.org/10.3389/fnins.2021.630502] [PMID: 33679311]
[18]
Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer’s disease. A meta-analysis. JAMA 1997; 278(16): 1349-56.
[http://dx.doi.org/10.1001/jama.1997.03550160069041] [PMID: 9343467]
[19]
Neu SC, Pa J, Kukull W, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer’s disease. JAMA Neurol 2017; 74(10): 1178-89.
[http://dx.doi.org/10.1001/jamaneurol.2017.2188] [PMID: 28846757]
[20]
White K, Yang P, Li L, Farshori A, Medina AE, Zielke HR. Effect of postmortem interval and years in storage on rna quality of tissue at a repository of the NIH NeuroBioBank. Biopreserv Biobank 2018; 16(2): 148-57.
[http://dx.doi.org/10.1089/bio.2017.0099] [PMID: 29498539]
[21]
Shen WB, Ni J, Yang P, Yao R, Goetzinger KR, Harman C. Maternal obesity-induced epigenetic alterations in human placenta. Reprod Toxicol 2022; 107: 90-6.
[22]
Xu C, Shen WB, Reece EA, et al. Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin. Sci Adv 2021; 7(27): eabf5089.
[http://dx.doi.org/10.1126/sciadv.abf5089] [PMID: 34193422]
[23]
Yang L, Yu SJ, Hong Q, Yang Y, Shao ZM. Reduced expression of TET1, TET2, TET3 and TDG mRNAs are associated with poor prognosis of patients with early breast cancer. PLoS One 2015; 10(7): e0133896.
[http://dx.doi.org/10.1371/journal.pone.0133896] [PMID: 26207381]
[24]
Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science 2018; 361(6409): 1346-9.
[http://dx.doi.org/10.1126/science.aau1646] [PMID: 30262497]
[25]
Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell 2017; 169(7): 1187-200.
[http://dx.doi.org/10.1016/j.cell.2017.05.045] [PMID: 28622506]
[26]
Geula S, Moshitch-Moshkovitz S, Dominissini D, et al. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science 2015; 347(6225): 1002-6.
[http://dx.doi.org/10.1126/science.1261417] [PMID: 25569111]
[27]
Zhang Z, Wang M, Xie D, et al. METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation. Cell Res 2018; 28(11): 1050-61.
[http://dx.doi.org/10.1038/s41422-018-0092-9] [PMID: 30297870]
[28]
Koranda JL, Dore L, Shi H, et al. Mettl14 is essential for epitranscriptomic regulation of striatal function and learning. Neuron 2018; 99(2): 283-292.e5.
[http://dx.doi.org/10.1016/j.neuron.2018.06.007] [PMID: 30056831]
[29]
Shafik AM, Allen EG, Jin P. Dynamic N6-methyladenosine RNA methylation in brain and diseases. Epigenomics 2020; 12(4): 371-80.
[http://dx.doi.org/10.2217/epi-2019-0260] [PMID: 32081027]
[30]
Wang Y, Li Y, Yue M, et al. N6-methyladenosine RNA modification regulates embryonic neural stem cell self-renewal through histone modifications. Nat Neurosci 2018; 21(2): 195-206.
[http://dx.doi.org/10.1038/s41593-017-0057-1] [PMID: 29335608]
[31]
Yoon KJ, Ringeling FR, Vissers C, et al. Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 2017; 171(4): 877-889.e17.
[http://dx.doi.org/10.1016/j.cell.2017.09.003] [PMID: 28965759]
[32]
Chang M, Lv H, Zhang W, et al. Region-specific RNA m6A methylation represents a new layer of control in the gene regulatory network in the mouse brain. Open Biol 2017; 7(9): 170166.
[http://dx.doi.org/10.1098/rsob.170166] [PMID: 28931651]
[33]
Ma C, Chang M, Lv H, et al. RNA m6A methylation participates in regulation of postnatal development of the mouse cerebellum. Genome Biol 2018; 19(1): 68.
[http://dx.doi.org/10.1186/s13059-018-1435-z] [PMID: 29855379]
[34]
Chen X, Yu C, Guo M, et al. Down regulation of m6A mRNA methylation is involved in dopaminergic neuronal death. ACS Chem Neurosci 2019; 10(5): 2355-63.
[http://dx.doi.org/10.1021/acschemneuro.8b00657] [PMID: 30835997]
[35]
Lin YT, Seo J, Gao F, et al. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 2018; 98(6): 1141-1154.e7.
[http://dx.doi.org/10.1016/j.neuron.2018.05.008] [PMID: 29861287]
[36]
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron 2009; 63(3): 287-303.
[http://dx.doi.org/10.1016/j.neuron.2009.06.026] [PMID: 19679070]
[37]
Shi Y, Yamada K, Liddelow SA, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 2017; 549(7673): 523-7.
[http://dx.doi.org/10.1038/nature24016] [PMID: 28959956]

Rights & Permissions Print Cite
Article Metrics
4
© 2024 Bentham Science Publishers | Privacy Policy