Epigenetics in Alzheimer’s Disease: Perspective of DNA Methylation

Abstract

Research over the years has shown that causes of Alzheimer’s disease are not well understood, but over the past years, the involvement of epigenetic mechanisms in the developing memory formation either under pathological or physiological conditions has become clear. The term epigenetics represents the heredity of changes in phenotype that are independent of altered DNA sequences. Different studies validated that cytosine methylation of genomic DNA decreases with age in different tissues of mammals, and therefore, the role of epigenetic factors in developing neurological disorders in aging has been under focus. In this review, we summarized and reviewed the involvement of different epigenetic mechanisms especially the DNA methylation in Alzheimer’s disease (AD), late-onset Alzheimer’s disease (LOAD), familial Alzheimer’s disease (FAD), and autosomal dominant Alzheimer’s disease (ADAD). Down to the minutest of details, we tried to discuss the methylation patterns like mitochondrial DNA methylation and ribosomal DNA (rDNA) methylation. Additionally, we mentioned some therapeutic approaches related to epigenetics, which could provide a potential cure for AD. Moreover, we reviewed some recent studies that validate DNA methylation as a potential biomarker and its role in AD. We hope that this review will provide new insights into the understanding of AD pathogenesis from the epigenetic perspective especially from the perspective of DNA methylation.

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References

  1. 1.

    Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158–b158. doi:10.1136/bmj.b158

    PubMed  Article  Google Scholar 

  2. 2.

    World Health Organization (2012) Dementia fact sheet no. 362. http://www.who.int/mediacentre/factsheets/fs362/en/. Accessed 8 Jun 2016

  3. 3.

    National Institute on Aging (2011) About Alzheimer’s disease: symptoms. http://www.nia.nih.gov/alzheimers/topics/symptoms. Accessed 8 Jun 2016

  4. 4.

    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344. doi:10.1056/NEJMra0909142

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Todd S, Barr S, Roberts M, Passmore AP (2013) Survival in dementia and predictors of mortality: a review. Int J Geriatr Psychiatry 28:1109–1124. doi:10.1002/gps.3946

    PubMed  Google Scholar 

  6. 6.

    Ballard C, Gauthier S, Corbett A et al (2011) Alzheimer’s disease. Lancet 377:1019–1031. doi:10.1016/S0140-6736(10)61349-9

    PubMed  Article  Google Scholar 

  7. 7.

    National Institute for Health and Care Excellence (NICE) (2016) Dementia diagnosis and assessment. National Institute for Health and Care Excellence (NICE)

  8. 8.

    National Institute on Aging (2006) More research needed on ways to prevent Alzheimer’s, panel finds. In: Natl. Inst. Aging. https://www.nia.nih.gov/alzheimers/announcements/2010/06/more-research-needed-ways-prevent-alzheimers-panel-finds

  9. 9.

    Holliday R (1994) Epigenetics: an overview. Dev Genet 15:453–457. doi:10.1002/dvg.1020150602

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Day JJ, Sweatt JD (2011) Epigenetic mechanisms in cognition. Neuron 70:813–829. doi:10.1016/j.neuron.2011.05.019

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Fischer A, Sananbenesi F, Mungenast A, Tsai L-H (2010) Targeting the correct HDAC(s) to treat cognitive disorders. Trends Pharmacol Sci 31:605–617. doi:10.1016/j.tips.2010.09.003

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Sananbenesi F, Fischer A (2009) The epigenetic bottleneck of neurodegenerative and psychiatric diseases. Biol Chem. doi:10.1515/BC.2009.131

    PubMed  Google Scholar 

  13. 13.

    Stilling RM, Fischer A (2011) The role of histone acetylation in age-associated memory impairment and Alzheimer’s disease. Neurobiol Learn Mem 96:19–26. doi:10.1016/j.nlm.2011.04.002

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Razin A, Riggs AD (1980) DNA methylation and gene function. Science 210:604–610. doi:10.1126/science.6254144

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    van Emburgh BO, Robertson KD (2008) DNA methyltransferases and methyl-CpG binding proteins as multifunctional regulators of chromatin structure and development in mammalian cells. In: Tost J (ed) Epigenetics. Caister Academic Press, Norfolk, pp. 22–61

    Google Scholar 

  16. 16.

    Schaefer M, Pollex T, Hanna K et al (2010) RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev 24:1590–1595. doi:10.1101/gad.586710

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Jalili M, Pati S, Rath B, et al. (2013) Effect of diet and nutrients on molecular mechanism of gene expression mediated by nuclear receptor and epigenetic modulation. Open Nutraceuticals J 27–34. doi:10.2174/1876396001306010027

  18. 18.

    Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257. doi:10.1016/S0092-8674(00)81656-6

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Wu H, Tao J, Sun YE (2012) Regulation and function of mammalian DNA methylation patterns: a genomic perspective. 11:240–250. doi:10.1093/bfgp/els011

  20. 20.

    Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476. doi:10.1038/nrg2341

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science (80- ) 324:929–930. doi:10.1126/science.1169786

    CAS  Article  Google Scholar 

  22. 22.

    Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935. doi:10.1126/science.1170116

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Xu GL, Wong J (2015) Oxidative DNA demethylation mediated by Tet enzymes. Natl Sci Rev 2:318–328. doi:10.1093/nsr/nwv029

    Article  Google Scholar 

  24. 24.

    Tan L, Shi YG (2012) Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 139:1895–1902. doi:10.1242/dev.070771

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Schonrock N, Ke YD, Humphreys D et al (2010) Neuronal microRNA deregulation in response to Alzheimer’s disease amyloid-beta. PLoS One. doi:10.1371/journal.pone.0011070

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Zovoilis A, Agbemenyah HY, Agis-Balboa RC et al (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308. doi:10.1038/emboj.2011.327

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Im H-I, Kenny PJ (2012) MicroRNAs in neuronal function and dysfunction. Trends Neurosci 35:325–334. doi:10.1016/j.tins.2012.01.004

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Delay C, Mandemakers W, Hébert SS (2012) MicroRNAs in Alzheimer’s disease. Neurobiol Dis 46:285–290. doi:10.1016/j.nbd.2012.01.003

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Fischer A (2014) Targeting histone-modifications in Alzheimer’s disease. What is the evidence that this is a promising therapeutic avenue? Neuropharmacology 80:95–102. doi:10.1016/j.neuropharm.2014.01.038

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Montesanto A, Dato S, Bellizzi D et al (2012) Epidemiological, genetic and epigenetic aspects of the research on healthy ageing and longevity. Immun Ageing 9:6. doi:10.1186/1742-4933-9-6

    PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Cruickshanks HA, McBryan T, Nelson DM, Vanderkraats ND, Shah PP et al (2013) Senescent cells harbour features of the cancer epigenome. Nat Cell Biol 15:1495–1506. doi:10.1038/ncb2879

  32. 32.

    Salta E, Sierksma A, Vanden Eynden E, De Strooper B (2016) miR-132 loss de-represses ITPKB and aggravates amyloid and TAU pathology in Alzheimer’s brain. EMBO Mol Med 8:1005–1018. doi:10.15252/emmm.201606520

  33. 33.

    Zhang W, Li J, Suzuki K et al (2015) A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163. doi:10.1126/science.aaa1356

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Cheung I, Shulha HP, Jiang Y et al (2010) Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proc Natl Acad Sci U S A 107:8824–8829. doi:10.1073/pnas.1001702107

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Liu L, Cheung TH, Charville GW et al (2013) Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging. Cell Rep 4:189–204. doi:10.1016/j.celrep.2013.05.043

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Pu M, Ni Z, Wang M et al (2015) Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev 29:718–731. doi:10.1101/gad.254144.114

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Southworth LK, Owen AB, Kim SK (2009) Aging mice show a decreasing correlation of gene expression within genetic modules. PLoS Genet 5:e1000776. doi:10.1371/journal.pgen.1000776

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Numata S, Ye T, Hyde TM et al (2012) DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet 90:260–272. doi:10.1016/j.ajhg.2011.12.020

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Hannum G, Guinney J, Zhao L et al (2013) Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol Cell 49:359–367. doi:10.1016/j.molcel.2012.10.016

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Horvath S (2013) DNA methylation age of human tissues and cell types. Genome Biol 14:R115. doi:10.1186/gb-2013-14-10-r115

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Klein HU, Bennett DA, de Jager PL (2016) The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism. Acta Neuropathol:1–12. doi:10.1007/s00401-016-1612-7

  42. 42.

    Horvath S, Mah V, Lu AT et al (2015) The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY) 7:294–306. doi:10.18632/aging.100742

    Article  Google Scholar 

  43. 43.

    Yang J, Yu L, Gaiteri C et al (2015) Association of DNA methylation in the brain with age in older persons is confounded by common neuropathologies. Int J Biochem Cell Biol 67:58–64. doi:10.1016/j.biocel.2015.05.009

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Fuke C, Shimabukuro M, Petronis A et al (2004) Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 68:196–204. doi:10.1046/j.1529-8817.2004.00081.x

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Vanyushin BF, Nemirovsky LE, Klimenko VV et al (1973) The 5-methylcytosine in DNA of rats. Tissue and age specificity and the changes induced by hydrocortisone and other agents. Gerontologia 19:138–152

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Wilson VL, Smith RA, Ma S, Cutler RG (1987) Genomic 5-methyldeoxycytidine decreases with age. J Biol Chem 262:9948–9951

    CAS  PubMed  Google Scholar 

  47. 47.

    Mastroeni D, Grover A, Delvaux E et al (2010) Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging 31:2025–2037. doi:10.1016/j.neurobiolaging.2008.12.005

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923. doi:10.1126/science.8346443

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Wang SC, Oeize B, Schumacher A (2008) Age-specific epigenetic drift in late-onset Alzheimer’s disease. PLoS One. doi:10.1371/journal.pone.0002698

    Google Scholar 

  50. 50.

    Bernstein AI, Lin Y, Street RC, et al. (2016) 5-Hydroxymethylation-associated epigenetic modifiers of Alzheimer’s disease modulate tau-induced neurotoxicity. 0:1–14. doi: 10.1093/hmg/ddw109

  51. 51.

    Shu L, Sun W, Li L et al (2016) Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer’s disease. BMC Genomics 17:381. doi:10.1186/s12864-016-2731-1

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Song C-X, Szulwach KE, Fu Y et al (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29:68–72. doi:10.1038/nbt.1732

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Irier HA, Jin P (2012) Dynamics of DNA methylation in aging and Alzheimer’s disease. DNA Cell Biol 31:S-42–S-48. doi:10.1089/dna.2011.1565

    Article  CAS  Google Scholar 

  54. 54.

    Lovestone S, Reynolds CH (1997) The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative process. Neuroscience 78:309–324. doi:10.1016/S0306-4522(96)00577-5

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Alonso A, Zaidi T, Novak M et al (2001) Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 98:6923–6928. doi:10.1073/pnas.121119298

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Dourlen P, Fernandez-Gomez FJ, Dupont C et al (2016) Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of tau pathology. Mol Psychiatry:1–10. doi:10.1038/mp.2016.59

  57. 57.

    Tohgi H, Utsugisawa K, Nagane Y et al (1999) The methylation status of cytosines in a tau gene promoter region alters with age to downregulate transcriptional activity in human cerebral cortex. Neurosci Lett 275:89–92

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Sontag E, Nunbhakdi-Craig V, Sontag J-M et al (2007) Protein phosphatase 2A methyltransferase links homocysteine metabolism with tau and amyloid precursor protein regulation. J Neurosci 27:2751–2759. doi:10.1523/JNEUROSCI.3316-06.2007

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Nicolia V, Fuso A, Cavallaro RA, Di A (2010) B vitamin deficiency promotes tau phosphorylation through regulation of GSK3β and PP2A. 19:895–907. doi:10.3233/JAD-2010-1284

  60. 60.

    Popkie AP, Zeidner LC, Albrecht AM et al (2010) Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem 285:41337–41347. doi:10.1074/jbc.M110.170704

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Zhou XW, Gustafsson JA, Tanila H et al (2008) Tau hyperphosphorylation correlates with reduced methylation of protein phosphatase 2A. Neurobiol Dis 31:386–394. doi:10.1016/j.nbd.2008.05.013

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Yoon SY, Choi HI, Choi JE et al (2007) Methotrexate decreases PP2A methylation and increases tau phosphorylation in neuron. Biochem Biophys Res Commun 363:811–816. doi:10.1016/j.bbrc.2007.09.060

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Zhang CE, Tian Q, Wei W et al (2008) Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus. Neurobiol Aging 29:1654–1665. doi:10.1016/j.neurobiolaging.2007.04.015

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Alzheimer’s Association. http://www.alz.org/alzheimers_disease_causes_risk_factors.asp. Accessed 4 Jun 2016

  65. 65.

    Mastroeni D, Grover A, Delvaux E et al (2011) Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 32:1161–1180. doi:10.1016/j.neurobiolaging.2010.08.017

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Liu H, Li W, Zhao S et al (2016) Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells. Eur J Nutr 55:1849–1862. doi:10.1007/s00394-015-1002-2

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Sibani S, Melnyk S, Pogribny IP et al (2002) Studies of methionine cycle intermediates (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in Min mice. Carcinogenesis 23:61–65. doi:10.1093/carcin/23.1.61

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Trasler J, Deng L, Melnyk S et al (2003) Impact of Dnmt1 deficiency, with and without low folate diets, on tumor numbers and DNA methylation in min mice. Carcinogenesis 24:39–45. doi:10.1093/carcin/24.1.39

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Bottiglieri T, Godfrey P, Flynn T et al (1990) Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine. J Neurol Neurosurg Psychiatry 53:1096–1098. doi:10.1136/jnnp.53.12.1096

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Morrison LD, Smith DD, Kish SJ (1996) Brain S-adenosylmethionine levels are severely decreased in Alzheimer’s disease. J Neurochem 67:1328–1331. doi:10.1046/j.1471-4159.1996.67031328.x

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Serot JM, Christmann D, Dubost T et al (2001) CSF-folate levels are decreased in late-onset AD patients. J Neural Transm 108:93–99. doi:10.1007/s007020170100

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Kennedy BP, Bottiglieri T, Arning E et al (2004) Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function. J Neural Transm 111:547–567. doi:10.1007/s00702-003-0096-5

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Coppedè F, Tannorella P, Pezzini I et al (2012) Folate, homocysteine, vitamin B12, and polymorphisms of genes participating in one-carbon metabolism in late-onset Alzheimer’s disease patients and healthy controls. Antioxid Redox Signal 17:195–204. doi:10.1089/ars.2011.4368

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Obeid R, McCaddon A, Herrmann W (2007) The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. 1590–1606

  75. 75.

    van Groen T (2010) DNA methylation and Alzheimer’s disease. In: Epigenetics of aging. New York, Springer New York, pp 315–326

  76. 76.

    Barthet G, Georgakopoulos A, Robakis NK (2012) Cellular mechanisms of γ-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166–175. doi:10.1016/j.pneurobio.2012.05.006

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Hollingworth P, Harold D, Jones L et al (2011) Alzheimer’s disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry 26:793–802. doi:10.1002/gps.2628

    PubMed  Article  Google Scholar 

  78. 78.

    Migliore L, Coppedè F (2009) Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res—Fundam Mol Mech Mutagen 667:82–97. doi:10.1016/j.mrfmmm.2008.10.011

    CAS  Article  Google Scholar 

  79. 79.

    Wolfe MS, Xia W, Ostaszewski BL et al (1999) Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398:513–517. doi:10.1038/19077

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Fuso A, Seminara L, Cavallaro RA et al (2005) S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 28:195–204. doi:10.1016/j.mcn.2004.09.007

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Scarpa S, Fuso A, D’Anselmi F, Cavallaro RA (2003) Presenilin 1 gene silencing by S-adenosylmethionine: a treatment for Alzheimer disease? FEBS Lett 541:145–148. doi:10.1016/S0014-5793(03)00277-1

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Piaceri I, Raspanti B, Tedde A et al (2015) Epigenetic modifications in Alzheimer’s disease: cause or effect? J Alzheimers Dis 43:1169–1173. doi:10.3233/JAD-141452

    PubMed  Google Scholar 

  83. 83.

    Liu W, Liu C, Zhu J et al (2012) MicroRNA-16 targets amyloid precursor protein to potentially modulate Alzheimer’s-associated pathogenesis in SAMP8 mice. Neurobiol Aging 33:522–534. doi:10.1016/j.neurobiolaging.2010.04.034

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Tohgi H, Utsugisawa K, Nagane Y et al (1999) Reduction with age in methylcytosine in the promoter region −224∼−101 of the amyloid precursor protein gene in autopsy human cortex. Mol Brain Res 70:288–292. doi:10.1016/S0169-328X(99)00163-1

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Barrachina M, Ferrer I (2009) DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. 68:880–891. doi:10.1097/NEN.0b013e3181af2e46

  86. 86.

    Brohede J, Rinde M, Winblad B, Graff C (2010) A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease. J Neurogenet 24:179–181. doi:10.3109/01677063.2010.503978

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Fuso A, Nicolia V, Cavallaro RA et al (2008) B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain S-adenosylmethionine, and enhances PS1 and BACE expression and amyloid-β deposition in mice. Mol Cell Neurosci 37:731–746. doi:10.1016/j.mcn.2007.12.018

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Lin H-C, Hsieh H-M, Chen Y-H, Hu M-L (2009) S-Adenosylhomocysteine increases beta-amyloid formation in BV-2 microglial cells by increased expressions of beta-amyloid precursor protein and presenilin 1 and by hypomethylation of these gene promoters. Neurotoxicology 30:622–627. doi:10.1016/j.neuro.2009.03.011

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Cong L, Jia J, Qin W et al (2014) Genome-wide analysis of DNA methylation in an APP/PS1 mouse model of Alzheimer’s disease. Acta Neurol Belg 114:195–206. doi:10.1007/s13760-013-0267-6

    PubMed  Article  Google Scholar 

  90. 90.

    Chen KL, Wang SSS, Yang YY et al (2009) The epigenetic effects of amyloid-β1-40 on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun 378:57–61. doi:10.1016/j.bbrc.2008.10.173

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Carboni L, Lattanzio F, Candeletti S et al (2015) Peripheral leukocyte expression of the potential biomarker proteins Bdnf, Sirt1, and Psen1 is not regulated by promoter methylation in Alzheimer’s disease patients. Neurosci Lett 605:44–48. doi:10.1016/j.neulet.2015.08.012

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Offe K (2006) The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci 26:1596–1603. doi:10.1523/JNEUROSCI.4946-05.2006

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Furuya TK, Da Silva PNO, Payão SLM et al (2012) SORL1 and SIRT1 mRNA expression and promoter methylation levels in aging and Alzheimer’s disease. Neurochem Int 61:973–975. doi:10.1016/j.neuint.2012.07.014

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Müerköster SS, Werbing V, Koch D et al (2008) Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma-epigenetic downregulation of caspases. Int J Cancer 123:1751–1760. doi:10.1002/ijc.23703

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Wilson AG (2008) Epigenetic regulation of gene expression in the inflammatory response and relevance to common diseases. J Periodontol 79:1514–1519. doi:10.1902/jop.2008.080172

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Xiong M, Zhang T, Zhang LM et al (2008) Caspase inhibition attenuates accumulation of β-amyloid by reducing β-secretase production and activity in rat brains after stroke. Neurobiol Dis 32:433–441. doi:10.1016/j.nbd.2008.08.007

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Sommer G, Kralisch S, Lipfert J et al (2009) Amyloid precursor protein expression is induced by tumor necrosis factor alpha in 3T3-L1 adipocytes. J Cell Biochem 108:1418–1422. doi:10.1002/jcb.22382

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Drzezga A, Grimmer T, Henriksen G (2009) Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease. i:1487–1494. doi:10.1212/WNL.0b013e3181a2e8d0

  99. 99.

    Caesar I, Gandy S (2012) Evidence that an APOE epsilon4 “double whammy” increases risk for Alzheimer’s disease. BMC Med 10:36. doi:10.1186/1741-7015-10-36

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Cruchaga C, Kauwe JSK, Nowotny P et al (2012) Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Hum Mol Genet 21:4558–4571. doi:10.1093/hmg/dds296

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Castellano JM, Kim J, Stewart FR et al (2011) Human APOE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med 3:89ra57. doi:10.1126/scitranslmed.3002156

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    de Bem CMBE, Pezzi JC, Borba EM et al (2016) The synergistic risk effect of apolipoprotein ε4 and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) haplotype for Alzheimer’s disease. Mol Biol Rep 43:653–658. doi:10.1007/s11033-016-3999-6

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Yu JT, Tan L (2012) The role of clusterin in Alzheimer’s disease: pathways, pathogenesis, and therapy. Mol Neurobiol 45:314–326. doi:10.1007/s12035-012-8237-1

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Schrijvers EMC, Koudstaal PJ, Hofman A, Breteler MMB (2011) Plasma clusterin and the risk of Alzheimer disease. JAMA 305:1322–1326. doi:10.1001/jama.2011.381

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Thambisetty M, Simmons A, Velayudhan L et al (2010) Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease. Arch Gen Psychiatry 67:739–748. doi:10.1001/archgenpsychiatry.2010.78

    PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Rauhala HE, Porkka KP, Saramäki OR et al (2008) Clusterin is epigenetically regulated in prostate cancer. Int J Cancer 123:1601–1609. doi:10.1002/ijc.23658

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Nuutinen T, Suuronen T, Kyrylenko S et al (2005) Induction of clusterin/apoJ expression by histone deacetylase inhibitors in neural cells. Neurochem Int 47:528–538. doi:10.1016/j.neuint.2005.07.007

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Suuronen T, Nuutinen T, Ryhänen T et al (2007) Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells. Biochem Biophys Res Commun 357:397–401. doi:10.1016/j.bbrc.2007.03.135

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Wang J, Yu J-T, Tan M-S et al (2013) Epigenetic mechanisms in Alzheimer’s disease: implications for pathogenesis and therapy. Ageing Res Rev 12:1024–1041. doi:10.1016/j.arr.2013.05.003

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Ding Q (2005) Ribosome dysfunction is an early event in Alzheimer’s disease. J Neurosci 25:9171–9175. doi:10.1523/JNEUROSCI.3040-05.2005

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Pietrzak M, Rempala G, Nelson PT, et al. (2011) Epigenetic silencing of nucleolar rRNA genes in Alzheimer’s disease. 6:1–10. doi:10.1371/journal.pone.0022585

  112. 112.

    Pietrzak M, Rempala GA, Nelson PT, Hetman M (2016) Non-random distribution of methyl-CpG sites and non-CpG methylation in the human rDNA promoter identified by next generation bisulfite sequencing. Gene 585:35–43. doi:10.1016/j.gene.2016.03.028

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Hansmannel F, Lendon C, Pasquier F et al (2009) Is the ornithine transcarbamylase gene a genetic determinant of Alzheimer’s disease? Neurosci Lett 449:76–80. doi:10.1016/j.neulet.2008.10.081

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Bensemain F, Hot D, Ferreira S et al (2009) Evidence for induction of the ornithine transcarbamylase expression in Alzheimer’s disease. Mol Psychiatry 14:106–116. doi:10.1038/sj.mp.4002089

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Kudriashova IB, Kirnos MD, Vaniushin BF (1976) DNA-methylase activities from animal mitochondria and nuclei: different specificity of DNA methylation. Biokhimiia (Moscow, Russ) 41:1968–1977

    CAS  Google Scholar 

  116. 116.

    Nass MMK (1973) Differential methylation of mitochondrial and nuclear DNA in cultured mouse, hamster and virus-transformed hamster cells in vivo and in vitro methylation. J Mol Biol 80:155–175. doi:10.1016/0022-2836(73)90239-8

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Reis RJS, Goldstein S (1983) Mitochondrial DNA in mortal and immortal human cells. J Biol Chem 258:9078–9085

    CAS  Google Scholar 

  118. 118.

    Shock LS, Thakkar PV, Peterson EJ et al (2011) DNA methyltransferase 1, cytosine methylation, and cytosine hydroxymethylation in mammalian mitochondria. Proc Natl Acad Sci 108:3630–3635. doi:10.1073/pnas.1012311108

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Choi Y-S, Hoon Jeong J, Min H-K et al (2011) Shot-gun proteomic analysis of mitochondrial D-loop DNA binding proteins: identification of mitochondrial histones. Mol BioSyst 7:1523. doi:10.1039/c0mb00277a

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Barrey E, Saint-Auret G, Bonnamy B et al (2011) Pre-microRNA and mature microRNA in human mitochondria. PLoS One 6:e20220. doi:10.1371/journal.pone.0020220

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Chestnut BA, Chang Q, Price A et al (2011) Epigenetic regulation of motor neuron cell death through DNA methylation. J Neurosci 31:16619–16636. doi:10.1523/JNEUROSCI.1639-11.2011

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Dzitoyeva S, Chen H, Manev H (2012) Effect of aging on 5-hydroxymethylcytosine in brain mitochondria. Neurobiol Aging 33:2881–2891. doi:10.1016/j.neurobiolaging.2012.02.006

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Iacobazzi V, Castegna A, Infantino V, Andria G (2013) Mitochondrial DNA methylation as a next-generation biomarker and diagnostic tool. Mol Genet Metab 110:25–34. doi:10.1016/j.ymgme.2013.07.012

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Manev H, Dzitoyeva S, Chen H (2012) Mitochondrial DNA: a blind spot in neuroepigenetics. 3:107–115. doi: 10.1515/bmc-2011-0058

  125. 125.

    Blanch M, Mosquera JL, Ansoleaga B et al (2016) Altered mitochondrial DNA methylation pattern in Alzheimer disease-related pathology and in Parkinson disease. Am J Pathol 186:385–397. doi:10.1016/j.ajpath.2015.10.004

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Halder R, Hennion M, Vidal RO et al (2015) DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci 19:102–110. doi:10.1038/nn.4194

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Liu HC, Hu CJ, Tang YC, Chang JG (2008) A pilot study for circadian gene disturbance in dementia patients. Neurosci Lett 435:229–233. doi:10.1016/j.neulet.2008.02.041

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Bollati V, Galimberti D, Pergoli L et al (2011) DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun 25:1078–1083. doi:10.1016/j.bbi.2011.01.017

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Khan AA, Mao XO, Banwait S et al (2007) Neuroglobin attenuates beta-amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo. Proc Natl Acad Sci U S A 104:19114–19119. doi:10.1073/pnas.0706167104

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Zhang W, Tian Z, Sha S et al (2011) Functional and sequence analysis of human neuroglobin gene promoter region. Biochim Biophys Acta 1809:236–244. doi:10.1016/j.bbagrm.2011.02.003 %/ 2011 Elsevier B.V. All rights reserved

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Guan J-Z, Guan W-P, Maeda T, Makino N (2012) Effect of vitamin E administration on the elevated oxygen stress and the telomeric and subtelomeric status in Alzheimer’s disease. Gerontology 58:62–69. doi:10.1159/000327821

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Rao JS, Keleshian VL, Klein S, Rapoport SI (2012) Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients. Transl Psychiatry 2:e132. doi:10.1038/tp.2012.55

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Roth ED, Roth TL, Money KM et al (2015) DNA methylation regulates neurophysiological spatial representation in memory formation. Neuroepigenetics 2:1–8. doi:10.1016/j.nepig.2015.03.001

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Silva PN, Furuya TK, Sampaio Braga I et al (2013) CNP and DPYSL2 mRNA expression and promoter methylation levels in brain of Alzheimer’s disease patients. J Alzheimers Dis 33:349–355. doi:10.3233/JAD-2012-121192

    CAS  PubMed  Google Scholar 

  135. 135.

    Silva PNO, Gigek CO, Leal MF et al (2008) Promoter methylation analysis of SIRT3, SMARCA5, HTERT and CDH1 genes in aging and Alzheimer’s disease. J Alzheimers Dis 13:173–176

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Furuya TK, Silva PNO, Payão SLM et al (2012) Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer’s disease patients. Neuroscience 220:41–46. doi:10.1016/j.neuroscience.2012.06.035

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Moreira PR, Guimarães MM, ALS G et al (2009) Methylation of P16, P21, P27, RB1 and P53 genes in odontogenic keratocysts. J Oral Pathol Med 38:99–103. doi:10.1111/j.1600-0714.2008.00718.x

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Tschöp K, Engeland K (2007) Cell cycle-dependent transcription of cyclin B2 is influenced by DNA methylation but is independent of methylation in the CDE and CHR elements. FEBS J 274:5235–5249. doi:10.1111/j.1742-4658.2007.06045.x

    PubMed  Article  CAS  Google Scholar 

  139. 139.

    Jee CD, Lee HS, Bae SI et al (2005) Loss of caspase-1 gene expression in human gastric carcinomas and cell lines. Int J Oncol 26:1265–1271

    CAS  PubMed  Google Scholar 

  140. 140.

    Robertson KD, Jones PA (1998) The human ARF cell cycle regulatory gene promoter is a CpG island which can be silenced by DNA methylation and down-regulated by wild-type p53. Mol Cell Biol 18:6457–6473

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Siegmund KD, Connor CM, Campan M et al (2007) DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One. doi:10.1371/journal.pone.0000895

    Google Scholar 

  142. 142.

    Zukin S (2009) Epigenetics. Alzheimers Dement 5:P146–P147. doi:10.1016/j.jalz.2009.05.502

    Article  Google Scholar 

  143. 143.

    Sanchez-Mut JV, Aso E, Panayotis N et al (2013) DNA methylation map of mouse and human brain identifies target genes in Alzheimer’s disease. Brain 136:3018–3027. doi:10.1093/brain/awt237

    PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Sanchez-Mut JV, Heyn H, Vidal E et al (2016) Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns. Transl Psychiatry 6:e718. doi:10.1038/tp.2015.214

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    De Jager PL, Srivastava G, Lunnon K et al (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17:1156–1163. doi:10.1038/nn.3786 http://www.nature.com/neuro/journal/v17/n9/abs/nn.3786.html#supplementary-information

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Lunnon K, Smith R, Hannon E et al (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17:1164–1170. doi:10.1038/nn.3782

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Shinagawa S, Kobayashi N, Nagata T et al (2016) DNA methylation in the NCAPH2/LMF2 promoter region is associated with hippocampal atrophy in Alzheimer’s disease and amnesic mild cognitive impairment patients. Neurosci Lett 629:33–37. doi:10.1016/j.neulet.2016.06.055

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Kobayashi N, Shinagawa S, Nagata T et al (2016) Development of biomarkers based on DNA methylation in the NCAPH2/LMF2 promoter region for diagnosis of Alzheimer’s disease and amnesic mild cognitive impairment. PLoS One 11:1–12. doi:10.1371/journal.pone.0146449

    Google Scholar 

  149. 149.

    Di Francesco A, Arosio B, Falconi A et al (2015) Global changes in DNA methylation in Alzheimer’s disease peripheral blood mononuclear cells. Brain Behav Immun 45:139–144. doi:10.1016/j.bbi.2014.11.002

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Ferri E, Arosio B, D’Addario C et al (2016) Gene promoter methylation and expression of Pin1 differ between patients with frontotemporal dementia and Alzheimer’s disease. J Neurol Sci 362:283–286. doi:10.1016/j.jns.2016.02.004

    CAS  PubMed  Article  Google Scholar 

  151. 151.

    Ji H, Wang Y, Jiang D et al (2016) Elevated DRD4 promoter methylation increases the risk of Alzheimer’s disease in males. Mol Med Rep 14:2732–2738. doi:10.3892/mmr.2016.5560

    CAS  PubMed  Article  Google Scholar 

  152. 152.

    Ma SL, Sang Tang NL, Wa Lam LC (2016) Association of gene expression and methylation of UQCRC1 to the predisposition of Alzheimer’s disease in a Chinese population. J Psychiatr Res 76:143–147. doi:10.1016/j.jpsychires.2016.02.010

    PubMed  Article  Google Scholar 

  153. 153.

    Watson CT, Roussos P, Garg P et al (2016) Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer’s disease. Genome Med 8:5. doi:10.1186/s13073-015-0258-8

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. 154.

    Moore DS The developing genome: an introduction to behavioral epigenetics

  155. 155.

    Sato T, Cesaroni M, Chung W et al (2016) Transcriptional selectivity of epigenetic therapy in cancer. Cancer Res. doi:10.1158/0008-5472.CAN-16-0834

    PubMed Central  Google Scholar 

  156. 156.

    Durga J, van Boxtel MP, Schouten EG et al (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369:208–216. doi:10.1016/S0140-6736(07)60109-3

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Haan MN, Miller JW, Aiello AE et al (2007) Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr 85:511–517

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Werneke U, Turner T, Priebe S (2012) Complementary medicines in psychiatry: review of effectiveness and safety complementary medicines in psychiatry review of effectiveness and safety. 109–121. doi: 10.1192/bjp.188.2.109

  159. 159.

    Stahl SM (2010) Fooling mother nature: epigenetics and novel treatments for psychiatric disorders. CNS Spectr 15:358–365

    PubMed  Article  Google Scholar 

  160. 160.

    Stahl SM (2010) Methylated spirits: epigenetic hypotheses of psychiatric disorders. CNS Spectr 15:220–230

    PubMed  Article  Google Scholar 

  161. 161.

    Cao X-J, Huang S-H, Wang M et al (2008) S-adenosyl-L-methionine improves impaired hippocampal long-term potentiation and water maze performance induced by developmental lead exposure in rats. Eur J Pharmacol 595:30–34. doi:10.1016/j.ejphar.2008.07.061

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Issa JPJ, Garcia-Manero G, Giles FJ et al (2004) Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 103:1635–1640. doi:10.1182/blood-2003-03-0687

    CAS  PubMed  Article  Google Scholar 

  163. 163.

    Momparler RL, Bouffard DY, Momparler LF et al (1997) Pilot phase I-II study on 5-aza-2′-deoxycytidine (decitabine) in patients with metastatic lung cancer. Anti-Cancer Drugs 8:358–368

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Kelly TK, De Carvalho DD, Jones PA (2010) Epigenetic modifications as therapeutic targets. Nat Biotechnol 28:1069–1078. doi:10.1038/nbt.1678

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. 165.

    Kumar D, Aggarwal M, Kaas GA et al (2015) Tet1 oxidase regulates neuronal gene transcription, active DNA hydroxy-methylation, object location memory, and threat recognition memory HHS public access. Neuroepigenetics 4:12–27. doi:10.1016/j.nepig.2015.10.002

    PubMed  PubMed Central  Article  Google Scholar 

  166. 166.

    Su Y, Ryder J, Li B, et al. (2004) Lithium, a common drug for bipolar disorder treatment, regulates amyloid- precursor protein processing. 6899–6908

  167. 167.

    Qing H, He G, Ly PTT et al (2008) Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J Exp Med 205:2781–2789. doi:10.1084/jem.20081588

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Kilgore M, Miller CA, Fass DM et al (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology 35:870–880. doi:10.1038/npp.2009.197

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Ricobaraza A, Cuadrado-Tejedor M, Pérez-Mediavilla A et al (2009) Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology 34:1721–1732. doi:10.1038/npp.2008.229

    CAS  PubMed  Article  Google Scholar 

  170. 170.

    Ricobaraza A, Cuadrado-Tejedor M, Marco S et al (2012) Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22:1040–1050. doi:10.1002/hipo.20883

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Peleg S, Sananbenesi F, Zovoilis A, et al. (2010) Altered histone acetylation is associated with age-dependent memory impairment in mice. Science (80-. ) 328

  172. 172.

    Nuutinen T, Suuronen T, Kauppinen A, Salminen A (2010) Valproic acid stimulates clusterin expression in human astrocytes: implications for Alzheimer’s disease. Neurosci Lett. doi:10.1016/j.neulet.2010.03.041

    PubMed  Google Scholar 

  173. 173.

    Vecsey CG, Hawk JD, Lattal KM, et al. (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J Neurosci 27

  174. 174.

    Ishimaru N, Fukuchi M, Hirai A et al (2010) Differential epigenetic regulation of BDNF and NT-3 genes by trichostatin A and 5-aza-2′-deoxycytidine in neuro-2a cells. Biochem Biophys Res Commun. doi:10.1016/j.bbrc.2010.02.139

    Google Scholar 

  175. 175.

    Tian F, Marini AM, Lipsky RH (2010) Effects of histone deacetylase inhibitor trichostatin A on epigenetic changes and transcriptional activation of Bdnf promoter 1 by rat hippocampal neurons. Ann N Y Acad Sci 1199:186–193. doi:10.1111/j.1749-6632.2009.05175.x

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Green KN, Steffan JS, Martinez-Coria H, et al. (2008) Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-Phosphotau. J Neurosci 28

  177. 177.

    Brahe C, Vitali T, Tiziano FD, et al. (2005) Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. 256–259. doi:10.1038/sj.ejhg.5201320

  178. 178.

    Marks PA, Xu W-S (2009) Histone deacetylase inhibitors: potential in cancer therapy. J Cell Biochem 107:600–608. doi:10.1002/jcb.22185

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. 179.

    Marks PA (2010) The clinical development of histone deacetylase inhibitors as targeted anticancer drugs. Expert Opin Investig Drugs 19:1049–1066. doi:10.1517/13543784.2010.510514

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Salminen A, Tapiola T, Korhonen P, Suuronen T (1998) Neuronal apoptosis induced by histone deacetylase inhibitors. Mol Brain Res 61:203–206. doi:10.1016/S0169-328X(98)00210-1

    CAS  PubMed  Article  Google Scholar 

  181. 181.

    Kelly-Sell MJ, Kim YH, Straus S et al (2012) The histone deacetylase inhibitor, romidepsin, suppresses cellular immune functions of cutaneous T-cell lymphoma patients. Am J Hematol 87:354–360. doi:10.1002/ajh.23112

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Rossi LE, Avila DE, Spallanzani RG et al (2012) Histone deacetylase inhibitors impair NK cell viability and effector functions through inhibition of activation and receptor expression. J Leukoc Biol 91:321–331. doi:10.1189/JLB.0711339

    CAS  PubMed  Article  Google Scholar 

  183. 183.

    Arrowsmith CH, Bountra C, Fish PV et al (2012) Epigenetic protein families: a new frontier for drug discovery. Nat Rev Drug Discov 11:384–400. doi:10.1038/nrd3674

    CAS  PubMed  Article  Google Scholar 

  184. 184.

    Trapp J, Meier R, Hongwiset D et al (2007) Structure–activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2:1419–1431. doi:10.1002/cmdc.200700003

    CAS  PubMed  Article  Google Scholar 

  185. 185.

    Haggarty SJ, Koeller KM, Wong JC et al (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci 100:4389–4394. doi:10.1073/PNAS.0430973100

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Ding H, Dolan PJ, Johnson GVW (2008) Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem 106:2119–2130. doi:10.1111/j.1471-4159.2008.05564.x

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. 187.

    Fang M, Wang J, Zhang X et al (2012) The miR-124 regulates the expression of BACE1/β-secretase correlated with cell death in Alzheimer’s disease. Toxicol Lett 209:94–105. doi:10.1016/j.toxlet.2011.11.032

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Zhu H-C, Wang L-M, Wang M et al (2012) MicroRNA-195 downregulates Alzheimer’s disease amyloid-β production by targeting BACE1. Brain Res Bull 88:596–601. doi:10.1016/j.brainresbull.2012.05.018

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Junn E, Mouradian MM (2012) MicroRNAs in neurodegenerative diseases and their therapeutic potential. Pharmacol Ther 133:142–150. doi:10.1016/j.pharmthera.2011.10.002

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Alvarez-Erviti L, Seow Y, Yin H et al (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345. doi:10.1038/nbt.1807

    CAS  PubMed  Article  Google Scholar 

  191. 191.

    Lakhal S, El Andaloussi S, O’Loughlin AJ, et al. (2013) RNAi therapeutic delivery by exosomes. Springer US, pp 185–205

  192. 192.

    Kuhn DE, Nuovo GJ, Terry AV et al (2010) Chromosome 21-derived microRNAs provide an etiological basis for aberrant protein expression in human down syndrome brains. J Biol Chem 285:1529–1543. doi:10.1074/jbc.M109.033407

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Bakulski KM, Dolinoy DC, Sartor MA et al (2012) Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 29:571–588. doi:10.3233/JAD-2012-111223

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Mr. Adil Farooq Lodhi (Department of Microbiology, Hazara University, Manshera, Pakistan) and Ms. Lucienne Duru (School of Life Science, Beijing Institute of Technology, Beijing, China) for their useful suggestions and support, which helped us completing this work. This work was supported by National Natural Science Foundation of China (NSFC 81671268) and Ministry of Science and Technology China (No. 2013YQ03059514).

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Qazi, T.J., Quan, Z., Mir, A. et al. Epigenetics in Alzheimer’s Disease: Perspective of DNA Methylation. Mol Neurobiol 55, 1026–1044 (2018). https://doi.org/10.1007/s12035-016-0357-6

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Keywords

  • DNA methylation
  • Epigenetic factors
  • Alzheimer’s disease
  • Histone modifications
  • ncRNAs
  • mtDNA methylation