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RNA m6A Methylation and Alzheimer's Disease: Current Evidence and Future Perspectives

  • Wenqi Pan
  • Yan Chen
  • Yuesi Xu
  • Wei-Min Tong
  • Yamei Niu

Abstract

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by the pathological accumulation of b-amyloid and neurofibrillary tangles. Despite substantial progress in both basic and clinical research on AD, the detailed mechanism of AD pathogenesis is still elusive. RNA N6-methyladenosine methylation (m6A) is the most predominant post-transcriptional modification on eukaryotic mRNA, prominently enriched in the mammalian brain. Notably, m6A-modified RNA showed significant changes during the development of AD, indicating an important role of this modification in AD pathogenesis.

Aim: In this study, we aim to provide a summary of recent advances highlighting the indispensable role of m6A in AD pathogenesis.

Result: From the perspective of m6A modification, we review our current understanding of the association between RNA m6A machinery and the risk factors of AD, as well as its involvement in various pathophysiological hallmarks of AD. We also discuss the main obstacles in current studies about m6A in AD pathogenesis and the corresponding caveats and solutions to them.

Conclusion: This review emphasizes the significance of investigating m6A in the context of AD and highlights the considerable potential for m6A to emerge as a novel therapeutic target for AD.

Section

References

  1. Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer's disease. Lancet. 2021;397(10284):1577-90.
  2. Ren R, Qi J, Lin S, Liu X, Yin P, Wang Z, et al. The China Alzheimer Report 2022. Gen Psychiatr. 2022;35(1):e100751.
  3. Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease. Lancet Neurol. 2011;10(2):187-98.
  4. Livneh I, Moshitch-Moshkovitz S, Amariglio N, Rechavi G, Dominissini D. The m6A epitranscriptome: transcriptome plasticity in brain development and function. Nat Rev Neurosci. 2020;21(1):36-51.
  5. Zhang N, Ding C, Zuo Y, Peng Y, Zuo L. N6-methyladenosine and Neurological Diseases. Mol Neurobiol. 2022;59(3):1925-37.
  6. Johnson R, Noble W, Tartaglia GG, Buckley NJ. Neurodegeneration as an RNA disorder. Progress in Neurobiology. 2012;99(3):293-315.
  7. Sendinc E, Shi Y. RNA m6A methylation across the transcriptome. Mol Cell. 2023;83(3):428-41.
  8. Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, et al. The U6 snRNA m6A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell. 2017;169(5).
  9. Ma H, Wang X, Cai J, Dai Q, Natchiar SK, Lv R, et al. N6-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat Chem Biol. 2019;15(1):88-94.
  10. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885-7.
  11. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang C-M, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18-29.
  12. Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 2019;20(10):608-24.
  13. Edupuganti RR, Geiger S, Lindeboom RGH, Shi H, Hsu PJ, Lu Z, et al. N6-methyladenosine (m6A) recruits and repels proteins to regulate mRNA homeostasis. Nature Structural & Molecular Biology. 2017;24(10):870-8.
  14. Wu R, Li A, Sun B, Sun J-G, Zhang J, Zhang T, et al. A novel m6A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res. 2019;29(1):23-41.
  15. Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nature Reviews Molecular Cell Biology. 2017;18(1):31-42.
  16. Chen P-C, Han X, Shaw TI, Fu Y, Sun H, Niu M, et al. Alzheimer's disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment. Nat Aging. 2022;2(10):923-40.
  17. Cooper TA, Wan L, Dreyfuss G. RNA and Disease. Cell. 2009;136(4):777-93.
  18. Adhikari S, Xiao W, Zhao Y-L, Yang Y-G. m(6)A: Signaling for mRNA splicing. RNA Biol. 2016;13(9):756-9.
  19. Nikom D, Zheng S. Alternative splicing in neurodegenerative disease and the promise of RNA therapies. Nat Rev Neurosci. 2023;24(8):457-73.
  20. Mofatteh M. mRNA localization and local translation in neurons. AIMS Neuroscience. 2020;7(3):299-310.
  21. Merkurjev D, Hong W-T, Iida K, Oomoto I, Goldie BJ, Yamaguti H, et al. Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts. Nature Neuroscience. 2018;21(7):1004-14.
  22. Zhuang M, Li X, Zhu J, Zhang J, Niu F, Liang F, et al. The m6A reader YTHDF1 regulates axon guidance through translational control of Robo3.1 expression. Nucleic Acids Res. 2019;47(9):4765-77.
  23. Yu J, She Y, Yang L, Zhuang M, Han P, Liu J, et al. The m6A Readers YTHDF1 and YTHDF2 Synergistically Control Cerebellar Parallel Fiber Growth by Regulating Local Translation of the Key Wnt5a Signaling Components in Axons. Advanced Science. 2021;8(22):2101329.
  24. Marcelo A, Koppenol R, de Almeida LP, Matos CA, Nóbrega C. Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation? Cell Death & Disease. 2021;12(6):592.
  25. Anders M, Chelysheva I, Goebel I, Trenkner T, Zhou J, Mao Y, et al. Dynamic m6A methylation facilitates mRNA triaging to stress granules. Life Sci Alliance. 2018;1(4):e201800113.
  26. Jiang L, Lin W, Zhang C, Ash PEA, Verma M, Kwan J, et al. Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy. Mol Cell. 2021;81(20).
  27. Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, et al. Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets. Science Advances. 2021;7(2):eabb5398.
  28. Cheng L, Vella LJ, Barnham KJ, McLean C, Masters CL, Hill AF. Small RNA fingerprinting of Alzheimer's disease frontal cortex extracellular vesicles and their comparison with peripheral extracellular vesicles. Journal of Extracellular Vesicles. 2020;9(1):1766822.
  29. Yoon KJ, Ringeling FR, Vissers C, Jacob F, Pokrass M, Jimenez-Cyrus D, et al. Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell. 2017;171(4):877-+.
  30. Li M, Zhao X, Wang W, Shi H, Pan Q, Lu Z, et al. Ythdf2-mediated m6A mRNA clearance modulates neural development in mice. Genome Biol. 2018;19(1):69.
  31. Culig L, Chu X, Bohr VA. Neurogenesis in aging and age-related neurodegenerative diseases. Ageing Research Reviews. 2022;78:101636.
  32. Chen J, Zhang Y-C, Huang C, Shen H, Sun B, Cheng X, et al. m6A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2. Genomics Proteomics Bioinformatics. 2019;17(2):154-68.
  33. Cao YH, Zhuang YL, Chen JC, Xu WZ, Shou YK, Huang XL, et al. Dynamic effects of Fto in regulating the proliferation and differentiation of adult neural stem cells of mice. Human Molecular Genetics. 2020;29(5):727-35.
  34. Zhang Z, Wang M, Xie D, Huang Z, Zhang L, Yang Y, et al. METTL3-mediated N6-methyladenosine mRNA modification enhances long-term memory consolidation. Cell Res. 2018;28(11):1050-61.
  35. Widagdo J, Zhao Q-Y, Kempen M-J, Tan MC, Ratnu VS, Wei W, et al. Experience-dependent accumulation of N6-methyladenosine in the prefrontal cortex is associated with memory processes in mice. Journal of Neuroscience. 2016;36(25):6771-7.
  36. Walters BJ, Mercaldo V, Gillon CJ, Yip M, Neve RL, Boyce FM, et al. The Role of The RNA Demethylase FTO (Fat Mass and Obesity-Associated) and mRNA Methylation in Hippocampal Memory Formation. Neuropsychopharmacology. 2017;42(7):1502-10.
  37. Shi H, Zhang X, Weng Y-L, Lu Z, Liu Y, Lu Z, et al. m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature. 2018;563(7730):249-53.
  38. Koranda JL, Dore L, Shi H, Patel MJ, Vaasjo LO, Rao MN, et al. Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning. Neuron. 2018;99(2).
  39. Silva MVF, Loures CdMG, Alves LCV, de Souza LC, Borges KBG, Carvalho MdG. Alzheimer's disease: risk factors and potentially protective measures. J Biomed Sci. 2019;26(1):33.
  40. Liu R-M. Aging, Cellular Senescence, and Alzheimer's Disease. Int J Mol Sci. 2022;23(4).
  41. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-217.
  42. Shafik AM, Zhang F, Guo Z, Dai Q, Pajdzik K, Li Y, et al. N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease. Genome Biol. 2021;22(1):17.
  43. Huang H, Song R, Wong JJL, Anggono V, Widagdo J. The N6-methyladenosine RNA landscape in the aged mouse hippocampus. Aging Cell. 2023;22(1):e13755.
  44. Castro-Hernández R, Berulava T, Metelova M, Epple R, Peña Centeno T, Richter J, et al. Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts. Proc Natl Acad Sci U S A. 2023;120(9):e2204933120.
  45. Koutsodendris N, Nelson MR, Rao A, Huang Y. Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms. Annual Review of Pathology: Mechanisms of Disease. 2022;17(1):73-99.
  46. Pires M, Rego AC. Apoe4 and Alzheimer's Disease Pathogenesis-Mitochondrial Deregulation and Targeted Therapeutic Strategies. Int J Mol Sci. 2023;24(1).
  47. Keller L, Xu W, Wang H-X, Winblad B, Fratiglioni L, Graff C. The Obesity Related Gene, FTO, Interacts with APOE, and is Associated with Alzheimer's Disease Risk: A Prospective Cohort Study. Journal of Alzheimer's Disease. 2011;23:461-9.
  48. Huang J, Sun W, Wang Z, Lv C, Zhang T, Zhang D, et al. FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner. Journal of Experimental & Clinical Cancer Research. 2022;41(1):42.
  49. Du B, Zhang Y, Liang M, Du Z, Li H, Fan C, et al. N6-methyladenosine (m6A) modification and its clinical relevance in cognitive dysfunctions. Aging (Albany NY). 2021;13(16):20716-37.
  50. Bennett S, Thomas AJ. Depression and dementia: Cause, consequence or coincidence? Maturitas. 2014;79(2):184-90.
  51. Lyketsos CG, Olin J. Depression in Alzheimer's disease: overview and treatment. Biological Psychiatry. 2002;52(3):243-52.
  52. Engel M, Eggert C, Kaplick PM, Eder M, Röh S, Tietze L, et al. The Role of m6A/m-RNA Methylation in Stress Response Regulation. Neuron. 2018;99(2):389-+.
  53. Joshi K, Wang DO, Gururajan A. The m6A-methylome in major depression: A bioinformatic analysis of publicly available datasets. Psychiatry Research Communications. 2022;2(4):100089.
  54. Milaneschi Y, Lamers F, Mbarek H, Hottenga JJ, Boomsma DI, Penninx BWJH. The effect of FTO rs9939609 on major depression differs across MDD subtypes. Molecular Psychiatry. 2014;19(9):960-2.
  55. Yao Y, Wen Y, Du T, Sun N, Deng H, Ryan J, et al. Meta-analysis indicates that SNP rs9939609 within FTO is not associated with major depressive disorder (MDD) in Asian population. J Affect Disord. 2016;193:27-30.
  56. Liu S, Xiu J, Zhu C, Meng K, Li C, Han R, et al. Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice. Nature Communications. 2021;12(1):6937.
  57. Du T, Rao S, Wu L, Ye N, Liu Z, Hu H, et al. An association study of the m6A genes with major depressive disorder in Chinese Han population. J Affect Disord. 2015;183:279-86.
  58. Huang R, Zhang Y, Bai Y, Han B, Ju M, Chen B, et al. N6-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1–Regulated Astrocyte Dysfunction and Depressive-like Behaviors. Biological Psychiatry. 2020;88(5):392-404.
  59. Yuan X, Yan F, Gao L-H, Ma Q-H, Wang J. Hypericin as a potential drug for treating Alzheimer's disease and type 2 diabetes with a view to drug repositioning. CNS Neurosci Ther. 2023;29(11):3307-21.
  60. Lei C, Li N, Chen J, Wang Q. Hypericin Ameliorates Depression-like Behaviors via Neurotrophin Signaling Pathway Mediating m6A Epitranscriptome Modification. Molecules [Internet]. 2023; 28(9).
  61. Bull MJ. Down Syndrome. N Engl J Med. 2020;382(24):2344-52.
  62. Wiseman FK, Al-Janabi T, Hardy J, Karmiloff-Smith A, Nizetic D, Tybulewicz VLJ, et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci. 2015;16(9):564-74.
  63. Zigman WB, Schupf N, Urv T, Zigman A, Silverman W. Incidence and temporal patterns of adaptive behavior change in adults with mental retardation. Am J Ment Retard. 2002;107(3):161-74.
  64. Shi W, Yang F, Dai R, Sun Y, Chu Y, Liao S, et al. METTL3-Mediated N6-Methyladenosine Modification Is Involved in the Dysregulation of NRIP1 Expression in Down Syndrome. Frontiers In Cell and Developmental Biology. 2021;9:621374.
  65. Katrin, Blondrath, Jennifer, H., Steel, Loukia, et al. The nuclear cofactor receptor interacting protein-140 (RIP140) regulates the expression of genes involved in Aβ generation. Neurobiology of Aging. 2016.
  66. Meneses A, Koga S, O'Leary J, Dickson DW, Bu G, Zhao N. TDP-43 Pathology in Alzheimer's Disease. Mol Neurodegener. 2021;16(1):84.
  67. McMillan M, Gomez N, Hsieh C, Bekier M, Li X, Miguez R, et al. RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia. Mol Cell. 2023;83(2):219-36.e7.
  68. Brett BL, Gardner RC, Godbout J, Dams-O’Connor K, Keene CD. Traumatic Brain Injury and Risk of Neurodegenerative Disorder. Biological Psychiatry. 2022;91(5):498-507.
  69. Wang Y, Mao J, Wang X, Lin Y, Hou G, Zhu J, et al. Genome-wide screening of altered m6A-tagged transcript profiles in the hippocampus after traumatic brain injury in mice. Epigenomics. 2019;11(7):805-19.
  70. Yu J, Zhang Y, Ma H, Zeng R, Liu R, Wang P, et al. Epitranscriptomic profiling of N6-methyladenosine-related RNA methylation in rat cerebral cortex following traumatic brain injury. Molecular Brain. 2020;13(1):11.
  71. Cheng J, Lin L, Yu J, Zhu X, Ma H, Zhao Y. N6-methyladenosine RNA is modified in the rat hippocampus following traumatic brain injury with hypothermia treatment. Front Neurosci. 2023;17:1069640.
  72. Ramos-Cejudo J, Wisniewski T, Marmar C, Zetterberg H, Blennow K, de Leon MJ, et al. Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine. 2018;28:21-30.
  73. DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. 2019;14(1):32.
  74. Paroni G, Bisceglia P, Seripa D. Understanding the Amyloid Hypothesis in Alzheimer's Disease. J Alzheimers Dis. 2019;68(2):493-510.
  75. Lee EK, Kim HH, Kuwano Y, Abdelmohsen K, Srikantan S, Subaran SS, et al. hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nature Structural & Molecular Biology. 2010;17(6):732-9.
  76. Kolisnyk B, Al-Onaizi M, Soreq L, Barbash S, Bekenstein U, Haberman N, et al. Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology. Cerebral Cortex. 2017;27(7):3553-67.
  77. Berson A, Barbash S, Shaltiel G, Goll Y, Hanin G, Greenberg DS, et al. Cholinergic-associated loss of hnRNP-A/B in Alzheimer's disease impairs cortical splicing and cognitive function in mice. Embo Molecular Medicine. 2012;4(8):730-42.
  78. Zhao F, Xu Y, Gao S, Qin L, Austria Q, Siedlak SL, et al. METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events. Mol Neurodegener. 2021;16(1):70.
  79. Tang Z, Cao J, Yao J, Fan X, Zhao J, Zhao M, et al. KDM1A-mediated upregulation of METTL3 ameliorates Alzheimer's disease via enhancing autophagic clearance of p-Tau through m6A-dependent regulation of STUB1. Free Radic Biol Med. 2023;195:343-58.
  80. Brier MR, Gordon B, Friedrichsen K, McCarthy J, Stern A, Christensen J, et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease. Science Translational Medicine. 2016;8(338):338ra66-ra66.
  81. Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M, Kim WS, et al. Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain. 2018;141(2):521-34.
  82. Huang H, Camats-Perna J, Medeiros R, Anggono V, Widagdo J. Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease. eNeuro. 2020;7(5).
  83. Li H, Ren Y, Mao K, Hua F, Yang Y, Wei N, et al. FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling. Biochem Biophys Res Commun. 2018;498(1):234-9.
  84. Zheng C, Yu G, Su Q, Wu L, Tang J, Lin X, et al. The deficiency of N6-methyladenosine demethylase ALKBH5 enhances the neurodegenerative damage induced by cobalt. Science of The Total Environment. 2023;881:163429.
  85. Qu M, Zuo L, Zhang M, Cheng P, Guo Z, Yang J, et al. High glucose induces tau hyperphosphorylation in hippocampal neurons via inhibition of ALKBH5-mediated Dgkh m6A demethylation: a potential mechanism for diabetic cognitive dysfunction. Cell Death & Disease. 2023;14(6):385.
  86. Huang J, Jiang B, Li G-W, Zheng D, Li M, Xie X, et al. m6A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation. Cell Rep. 2022;41(8):111693.
  87. Dhakal S, Macreadie I. Protein Homeostasis Networks and the Use of Yeast to Guide Interventions in Alzheimer’s Disease. Int J Mol Sci. 2020;21(21):8014.
  88. Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366(6467):818-22.
  89. López Salon M, Morelli L, Castaño EM, Soto EF, Pasquini JM. Defective ubiquitination of cerebral proteins in Alzheimer's disease. Journal of Neuroscience Research. 2000;62(2):302-10.
  90. Masayuki K, Hiroshi K, Ryo S, Yoshihisa K, Yasunobu O, Yasuyuki N. Loss of HRD1-Mediated Protein Degradation Causes Amyloid Precursor Protein Accumulation and Amyloid-β Generation. The Journal of Neuroscience. 2010;30(11):3924.
  91. Gireud-Goss M, Reyes S, Tewari R, Patrizz A, Howe MD, Kofler J, et al. The ubiquitin ligase UBE4B regulates amyloid precursor protein ubiquitination, endosomal trafficking, and amyloid β42 generation and secretion. Molecular and Cellular Neuroscience. 2020;108:103542.
  92. Gong B, Chen F, Pan Y, Arrieta-Cruz I, Yoshida Y, Haroutunian V, et al. SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. Aging Cell. 2010;9(6):1018-31.
  93. Salminen A, Ojala J, Kaarniranta K, Hiltunen M, Soininen H. Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease. Progress in Neurobiology. 2011;93(1):99-110.
  94. Xie M, Han Y, Yu Q, Wang X, Wang S, Liao X. UCH-L1 Inhibition Decreases the Microtubule-Binding Function of Tau Protein. Journal of Alzheimer's Disease. 2016;49:353-63.
  95. Zheng H, Zheng W-J, Wang Z-G, Tao Y-P, Huang Z-P, Yang L, et al. Corrigendum: Decreased expression of programmed death ligand-L1 by seven in absentia homolog 2 in cholangiocarcinoma enhances T-cell-mediated antitumor activity. Front Immunol. 2022;13:1093403.
  96. Yadav P, Subbarayalu P, Medina D, Nirzhor S, Timilsina S, Rajamanickam S, et al. M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression. Cancer Res. 2022;82(10):1872-89.
  97. Xia L, Han Q, Duan X, Zhu Y, Pan J, Dong B, et al. m6A-induced repression of SIAH1 facilitates alternative splicing of androgen receptor variant 7 by regulating CPSF1. Mol Ther Nucleic Acids. 2022;28:219-30.
  98. Wang X, Xie J, Tan L, Lu Y, Shen N, Li J, et al. N6-methyladenosine-modified circRIMS2 mediates synaptic and memory impairments by activating GluN2B ubiquitination in Alzheimer's disease. Translational Neurodegeneration. 2023;12(1):53.
  99. Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, et al. Autophagy in healthy aging and disease. Nat Aging. 2021;1(8):634-50.
  100. Zhang W, Xu C, Sun J, Shen H-M, Wang J, Yang C. Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential. Acta Pharmaceutica Sinica B. 2022;12(3):1019-40.
  101. Inoue K, Rispoli J, Kaphzan H, Klann E, Chen EI, Kim J, et al. Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. Mol Neurodegener. 2012;7(1):1-13.
  102. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885-9.
  103. Rocchi A, Yamamoto S, Ting T, Fan Y, Sadleir K, Wang Y, et al. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer's disease. PLOS Genetics. 2017;13(8):e1006962.
  104. Wang X, Wu R, Liu Y, Zhao Y, Bi Z, Yao Y, et al. m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy. 2020;16(7):1221-35.
  105. Chen X, Gong W, Shao X, Shi T, Zhang L, Dong J, et al. METTL3-mediated m6A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis. 2022;81(1):87-99.
  106. He M, Lei H, He X, Liu Y, Wang A, Ren Z, et al. METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis. Stem Cells Transl Med. 2022;11(9).
  107. Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017;61(6):585-96.
  108. Jin S, Zhang X, Miao Y, Liang P, Zhu K, She Y, et al. m6A RNA modification controls autophagy through upregulating ULK1 protein abundance. Cell Res. 2018;28(9):955-7.
  109. Hao W, Dian M, Zhou Y, Zhong Q, Pang W, Li Z, et al. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA. Nature Communications. 2022;13(1):5845.
  110. Majumder S, Richardson A, Strong R, Oddo S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PloS one. 2011;6(9):e25416.
  111. Chang M, Lv H, Zhang W, Ma C, He X, Zhao S, et al. Region-specific RNA m6A methylation represents a new layer of control in the gene regulatory network in the mouse brain. Open Biology. 2017;7(9):170166.
  112. Leonetti AM, Chu MY, Ramnaraign FO, Holm S, Walters BJ. An Emerging Role of m6A in Memory: A Case for Translational Priming. Int J Mol Sci. 2020;21(20).
  113. Yu J, Chen M, Huang H, Zhu J, Song H, Zhu J, et al. Dynamic m6A modification regulates local translation of mRNA in axons. Nucleic Acids Res. 2018;46(3):1412-23.
  114. Flamand MN, Meyer KD. m6A and YTHDF proteins contribute to the localization of select neuronal mRNAs. Nucleic Acids Res. 2022;50(8):4464-83.
  115. Martinez De La Cruz B, Markus R, Malla S, Haig MI, Gell C, Sang F, et al. Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging. Molecular Psychiatry. 2021;26(12):7141-53.
  116. Zhuang M, Geng X, Han P, Che P, Liang F, Liu C, et al. YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory. Molecular Psychiatry. 2023;28(4):1679-91.
  117. Zhang X, Yang S, Han S, Sun Y, Han M, Zheng X, et al. Differential methylation of circRNA m6A in an APP/PS1 Alzheimer's disease mouse model. Molecular Medicine Reports. 2023;27(2).
  118. Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers & Dementia. 2016;12(6):719-32.
  119. Teng Y, Yi J, Chen J, Yang L. N6-Methyladenosine (m6A) Modification in Natural Immune Cell-Mediated Inflammatory Diseases. Journal of Innate Immunity. 2023;15(1):804-21.
  120. Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. Journal of Cell Biology. 2018;217(2):459-72.
  121. Kwon HS, Koh S-H. Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational Neurodegeneration. 2020;9(1):42.
  122. Li Q, Wen S, Ye W, Zhao S, Liu X. The potential roles of m6A modification in regulating the inflammatory response in microglia. Journal of Neuroinflammation. 2021;18(1):149.
  123. He S, Li W, Wang G, Wang X, Fan W, Zhang Z, et al. FTO-mediated m6A modification alleviates autoimmune uveitis by regulating microglia phenotypes via the GPC4/TLR4/NF-κB signaling axis. Genes & Diseases. 2023;10(5):2179-93.
  124. Zhou HX, Xu ZR, Liao XY, Tang SY, Li N, Hou SP. Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA. Frontiers in Cellular Neuroscience. 2021;15.
  125. Ding L, Wu HR, Wang Y, Li Y, Liang ZP, Xia XH, et al. m6A Reader Igf2bp1 Regulates the Inflammatory Responses of Microglia by Stabilizing Gbp11 and Cp mRNAs. Frontiers in Immunology. 2022;13.
  126. Chen Y, Colonna M. Microglia in Alzheimer's disease at single-cell level. Are there common patterns in humans and mice? Journal of Experimental Medicine. 2021;218(9).
  127. Fernández Zapata C, Giacomello G, Spruth EJ, Middeldorp J, Gallaccio G, Dehlinger A, et al. Differential compartmentalization of myeloid cell phenotypes and responses towards the CNS in Alzheimer’s disease. Nature Communications. 2022;13(1):7210.
  128. Yin H, Ju Z, Zheng M, Zhang X, Zuo W, Wang Y, et al. Loss of the m6A methyltransferase METTL3 in monocyte-derived macrophages ameliorates Alzheimer's disease pathology in mice. PLoS Biol. 2023;21(3):e3002017.
  129. Leng F, Edison P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nature Reviews Neurology. 2021;17(3):157-72.
  130. Li Z, Chen Z, Peng J. Neural stem cell-derived exosomal FTO protects neuron from microglial inflammatory injury by inhibiting microglia NRF2 mRNA m6A modification. J Neurogenet. 2023;37(3):103-14.
  131. Guo X, Qiu W, Li B, Qi Y, Wang S, Zhao R, et al. Hypoxia-induced neuronal activity in glioma patients polarizes microglia by potentiating RNA m6A demethylation. Clin Cancer Res. 2023.
  132. Cockova Z, Honc O, Telensky P, Olsen MJ, Novotny J. Streptozotocin-Induced Astrocyte Mitochondrial Dysfunction Is Ameliorated by FTO Inhibitor MO-I-500. ACS Chem Neurosci. 2021;12(20):3818-28.
  133. Weidling IW, Swerdlow RH. Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis. Experimental Neurology. 2020;330.
  134. Delaunay S, Pascual G, Feng B, Klann K, Behm M, Hotz-Wagenblatt A, et al. Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature. 2022;607(7919):593-603.
  135. Mota BC, Sastre M. The Role of PGC1α in Alzheimer's Disease and Therapeutic Interventions. Int J Mol Sci. 2021;22(11).
  136. Zhang XN, Li X, Jia HT, An GS, Ni JH. The m6A methyltransferase METTL3 modifies PGC-1α mRNA promoting mitochondrial dysfunction and oxLDL-induced inflammation in monocytes. Journal of Biological Chemistry. 2021;297(3).
  137. Sun L, Wan A, Zhou ZL, Chen DS, Liang H, Liu CW, et al. RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer. Gut. 2021;70(9):1698-712.
  138. Yang P, Wang Y, Ge W, Jing Y, Hu H, Yin J, et al. m6A methyltransferase METTL3 contributes to sympathetic hyperactivity post-MI via promoting TRAF6-dependent mitochondrial ROS production. Free Radical Biology and Medicine. 2023;209:342-54.
  139. Du YD, Guo WY, Han CH, Wang Y, Chen XS, Li DW, et al. N6-methyladenosine demethylase FTO impairs hepatic ischemia–reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation. Cell Death & Disease. 2021;12(5):442.
  140. Deng P, Zhang H, Wang L, Jie S, Zhao Q, Chen F, et al. Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532/m6A/FIS1 axis-mediated mitochondrial fission and dysfunction. Science of The Total Environment. 2023;858:159950.
  141. Johri A. Disentangling Mitochondria in Alzheimer's Disease. International Journal of Molecular Sciences. 2021;22(21).
  142. Zhong X, Yu J, Frazier K, Weng X, Li Y, Cham CM, et al. Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation. Cell Rep. 2018;25(7):1816-28.e4.
  143. Yu F, Wei J, Cui X, Yu C, Ni W, Bungert J, et al. Post-translational modification of RNA m6A demethylase ALKBH5 regulates ROS-induced DNA damage response. Nucleic Acids Res. 2021;49(10):5779-97.
  144. Linnebank M, Popp J, Smulders Y, Smith D, Semmler A, Farkas M, et al. S-Adenosylmethionine Is Decreased in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease. Neurodegenerative Diseases. 2010;7(6):373-8.
  145. Niu Y, Zhao X, Wu Y-S, Li M-M, Wang X-J, Yang Y-G. N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genomics Proteomics Bioinformatics. 2013;11(1).
  146. Zhu D, Li X, Tian Y. Mitochondrial-to-nuclear communication in aging: an epigenetic perspective. Trends Biochem Sci. 2022;47(8):645-59.
  147. Zhang F, Zhong R-j, Cheng C, Li S, Le W-d. New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease. Acta Pharmacologica Sinica. 2021;42(9):1382-9.
  148. Mahaman YAR, Embaye KS, Huang F, Li L, Zhu F, Wang J-Z, et al. Biomarkers used in Alzheimer’s disease diagnosis, treatment, and prevention. Ageing Research Reviews. 2022;74:101544.
  149. Riscado M, Baptista B, Sousa F. New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics. Pharmaceutics [Internet]. 2021; 13(9).
  150. Self WK, Holtzman DM. Emerging diagnostics and therapeutics for Alzheimer disease. Nature Medicine. 2023;29(9):2187-99.
  151. Anthony K. RNA-based therapeutics for neurological diseases. RNA Biol. 2022;19(1):176-90.
  152. Jiang L, Roberts R, Wong M, Zhang L, Webber CJ, Kilci A, et al. Accumulation of m6A exhibits stronger correlation with MAPT than β-amyloid pathology in an APPNL-G-F /MAPTP301S mouse model of Alzheimer's disease. Res Sq. 2023.
  153. Yang L, Pang X, Guo W, Zhu C, Yu L, Song X, et al. An Exploration of the Coherent Effects between METTL3 and NDUFA10 on Alzheimer’s Disease. Int J Mol Sci [Internet]. 2023; 24(12).
  154. Zhang H, Chen K, Wang N, Zhang D, Yang Q, Zhang Q, et al. Analysis of Brain Donors' Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China. J Alzheimers Dis. 2018;66(3):1245-54.
  155. Boulias K, Greer EL. Means, mechanisms and consequences of adenine methylation in DNA. Nature Reviews Genetics. 2022;23(7):411-28.
  156. Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G. Transcriptome-wide mapping of N6-methyladenosine by m6A-seq based on immunocapturing and massively parallel sequencing. Nature Protocols. 2013;8(1):176-89.
  157. Meyer Kate D, Saletore Y, Zumbo P, Elemento O, Mason Christopher E, Jaffrey Samie R. Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons. Cell. 2012;149(7):1635-46.
  158. Yao H, Gao C-C, Zhang D, Xu J, Song G, Fan X, et al. scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development. Nature Communications. 2023;14(1):315.
  159. Liu C, Sun H, Yi Y, Shen W, Li K, Xiao Y, et al. Absolute quantification of single-base m6A methylation in the mammalian transcriptome using GLORI. Nature Biotechnology. 2023;41(3):355-66.
  160. Tegowski M, Zhu H, Meyer KD. Detecting m6A with In Vitro DART-Seq. Methods Mol Biol. 2022;2404:363-74.
  161. Hu L, Liu S, Peng Y, Ge R, Su R, Senevirathne C, et al. m6A RNA modifications are measured at single-base resolution across the mammalian transcriptome. Nature Biotechnology. 2022;40(8):1210-9.

How to Cite

Pan, Wenqi, et al. “RNA m6A Methylation and Alzheimer’s Disease: Current Evidence and Future Perspectives”. Human Brain, vol. 3, no. 1, Mar. 2024, doi:10.37819/hb.1.1796.

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DOI: https://doi.org/10.37819/hb.1.1796

Published: 2024-03-15

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Copyright (c) 2024 Wenqi Pan, Yan Chen, Yuesi Xu, Wei-Min Tong, Yamei Niu

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