The role for oxidative stress in aberrant DNA methylation in Alzheimer's disease

Current Alzheimer Research

Volumn 9, Issue 9, 2012, Pages 1077-1096

  Fleming, Jessica L ^a   Phiel, Christopher J ^a   Toland, Amanda Ewart ^a,b  

^a OHIO STATE UNIVERSITY   (United States)

^b OHIO STATE UNIVERSITY   (United States)

Author keywords

Alzheimer's disease; DNA methylation; Epigenetics; Gene regulation; Oxidative stress

Indexed keywords

AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; BETA SECRETASE 1; BETA SECRETASE INHIBITOR; CYCLIN B1; CYCLIN DEPENDENT KINASE 5; DNA METHYLTRANSFERASE 1; DNA METHYLTRANSFERASE 3A; DNA METHYLTRANSFERASE 3B; GLUTATHIONE; HOMOCYSTEINE; MEMBRANE METALLOENDOPEPTIDASE; METHIONINE ADENOSYLTRANSFERASE; PHOSPHOLIPID HYDROPEROXIDE GLUTATHIONE PEROXIDASE; PRESENILIN 1; REACTIVE OXYGEN METABOLITE; S ADENOSYLMETHIONINE; STRESS ACTIVATED PROTEIN KINASE;

AGING; ALZHEIMER DISEASE; APOPTOSIS; CARBON METABOLISM; CPG ISLAND; DEMETHYLATION; DNA DAMAGE; DNA METHYLATION; DNA REPAIR; ENZYME ACTIVITY; EXCISION REPAIR; GENE CONTROL; GENE EXPRESSION; HUMAN; HYPERHOMOCYSTEINEMIA; IMMUNOPATHOGENESIS; LIFESPAN; MILD COGNITIVE IMPAIRMENT; MULTIINFARCT DEMENTIA; NERVE CELL PLASTICITY; NEUROBLASTOMA; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW;

ALZHEIMER DISEASE; DNA METHYLATION; EPIGENESIS, GENETIC; HUMANS; OXIDATIVE STRESS;

EID: 84870163187     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/156720512803569000     Document Type: Review

References (220)

1. Available from: www.nia.nih.gov/Alzheimers
2. Lee HG, Zhu X, Castellani RJ, Nunomura A, Perry G, Smith MA. Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses. J Pharmacol Exp Ther 321: 823-829 (2007).
3. Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice. Nat Genet 25: 294-297 (2000).
4. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, et al. Gene regulation and DNA damage in the ageing human brain. Nature 429: 883-891 (2004).
5. Fehlbaum-Beurdeley P, Jarrige-Le Prado AC, Pallares D, Carriere J, Guihal C, Soucaille C, et al. Toward an Alzheimer's disease diagnosis via high-resolution blood gene expression. Alzheimers Dement 6: 25-38 (2010).
6. Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, et al. Expression of APP pathway mRNAs and proteins in Alzheimer's disease. Brain Res 1161:116-123 (2007).
7. Finkelstein JD. The metabolism of homocysteine: pathways and regulation. Eur J Pediatr 157: S40-S44 (1998).
8. Hajjar KA. Homocysteine: a sulph'rous fire. J Clin Invest 107: 663-664 (2001).
9. Chiang PK, Gordon RK, Tal J, Zeng GC, Doctor BP, Pardhasaradhi K, et al. S-Adenosylmethionine and methylation. FASEB J 10: 471-4780 (1996).
10. Illingworth RS, Bird AP. CpG islands--'a rough guide'. FEBS Lett 583: 1713-1720 (2009).
11. Asada K, Kotake Y, Asada R, Saunders D, Broyles RH, Towner RA, et al. LINE-1 hypomethylation in a choline-deficiencyinduced liver cancer in rats: dependence on feeding period. J Biomed Biotechnol 17142 (2006).
12. Yang AS, Estecio MR, Doshi K, Kondo Y, Tajara EH, Issa JP. A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32: e38 (2004).
13. Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmuhl Y, Fischer D, et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12: 1559-1566 (2009).
14. Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC. Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 38: 78-84 (2003).
15. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308: 1466-1449 (2005).
16. Fang JY, Xiao SD. Folic acid, polymorphism of methyl-group metabolism genes, and DNA methylation in relation to GI carcinogenesis. J Gastroenterol 38: 821-829 (2003).
17. Jamaluddin MS, Yang X, Wang H. Hyperhomocysteinemia, DNA methylation and vascular disease. Clin Chem Lab Med 45: 1660-1666 (2007).
18. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, et al. Induction of tumors in mice by genomic hypomethylation. Science 300: 489-492 (2003).
19. Tuck-Muller CM, Narayan A, Tsien F, Smeets DF, Sawyer J, Fiala ES, et al. DNA hypomethylation and unusual chromosome instability in cell lines from ICF syndrome patients. Cytogenet Cell Genet 89: 121-128 (2000).
20. Metivier R, Gallais R, Tiffoche C, Le Peron C, Jurkowska RZ, Carmouche RP, et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature 452: 45-50 (2008).
21. Kim MS, Kondo T, Takada I, Youn MY, Yamamoto Y, Takahashi S, et al. DNA demethylation in hormone-induced transcriptional derepression. Nature 461: 1007-1012 (2009).
22. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4: 235-240 (2003).
23. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302: 890-893 (2003).
24. Morgan HD, Santos F, Green K, Dean W, Reik W. Epigenetic reprogramming in mammals. Hum Mol Genet 14: R47-R58 (2005).
25. Wrenzycki C, Herrmann D, Lucas-Hahn A, Gebert C, Korsawe K, Lemme E, et al. Epigenetic reprogramming throughout preimplantation development and consequences for assisted reproductive technologies. Birth Defects Res C Embryo Today 75: 1-9 (2005).
26. Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development. Science 293: 1089-1093 (2001).
27. Zin'kovskaia GG, Berdyshev GD, Vaniushin BF. Tissue-specific decrease and change in the character of DNA methylation in cattle with aging. Biokhimiia 43: 1883-1892 (1978).
28. Wilson VL, Smith RA, Ma S, Cutler RG. Genomic 5- methyldeoxycytidine decreases with age. J Biol Chem 262: 9948-9951 (1987).
29. Wilson VL, Jones PA. DNA methylation decreases in aging but not in immortal cells. Science 220: 1055-1057 (1983).
30. Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, et al. Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130: 234-239 (2009).
31. Issa JP. Age-related epigenetic changes and the immune system. Clin Immunol 109: 103-108 (2003).
32. Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, et al. Aging and environmental exposures alter tissuespecific DNA methylation dependent upon CpG island context. PLoS Genet 58: e1000602 (2009).
33. Siegmund KD, Connor CM, Campan M, Long TI, Weisenberger DJ, Biniszkiewicz D, et al. DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One 2: e895 (2007).
34. Ladd-Acosta C, Pevsner J, Sabunciyan S, Yolken RH, Webster MJ, Dinkins T, et al. DNA methylation signatures within the human brain. Am J Hum Genet 81: 1304-1315 (2007).
35. Lahiri DK, Maloney B. The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Exp Gerontol 45: 291-296 (2010).
36. Martin GM. Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of aging. Aging Cell 8: 761-764 (2009).
37. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102: 10604-10609 (2005).
38. Li E, Bestor TH, Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 1992 69: 915-926 (1992).
39. Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99: 247-257 (1999).
40. Goto K, Numata M, Komura JI, Ono T, Bestor TH, Kondo H. Expression of DNA methyltransferase gene in mature and immature neurons as well as proliferating cells in mice. Differentiation 56: 39-44 (1994).
41. Inano K, Suetake I, Ueda T, Miyake Y, Nakamura M, Okada M, et al. Maintenance-type DNA methyltransferase is highly expressed in post-mitotic neurons and localized in the cytoplasmic compartment. J Biochem 128: 315-321 (2000).
42. Westberry JM, Trout AL, Wilson ME. Epigenetic regulation of estrogen receptor alpha gene expression in the mouse cortex during early postnatal development. Endocrinology 151: 731-740 (2010).
43. Fan G, Beard C, Chen RZ, Csankovszki G, Sun Y, Siniaia M, et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J Neurosci 21: 788-797 (2001).
44. Feng J, Chang H, Li E, Fan G. Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 79: 734-746 (2005).
45. Rai K, Jafri IF, Chidester S, James SR, Karpf AR, Cairns BR, et al. Dnmt3 and G9a cooperate for tissue-specific development in zebrafish. J Biol Chem 285: 4110-4121 (2010).
46. Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, et al. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 13: 423-430 (2010).
47. Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD. Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease. PLoS One 4: e6617 (2009).
48. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J. Epigenetic changes in Alzheimer's disease: Decrements in DNA methylation. Neurobiol Aging 31: 2025-2037 (2010).
49. Chen KL, Wang SS, Yang YY, Yuan RY, Chen RM, Hu CJ. The epigenetic effects of amyloid-beta(1-40) on global DNA and neprilysin genes in murine cerebral endothelial cells. Biochem Biophys Res Commun 378: 57-61 (2009).
50. Wang SC, Oelze B, Schumacher A. Age-specific epigenetic drift in late-onset Alzheimer's disease. PLoS One 3: e2698 (2008).
51. Morrison LD, Smith DD, Kish SJ. Brain S-adenosylmethionine levels are severely decreased in Alzheimer's disease. J Neurochem 67: 1328-1331 (1996).
52. Bottiglieri T, Godfrey P, Flynn T, Carney MW, Toone BK, Reynolds EH. Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral Sadenosylmethionine. J Neurol Neurosurg Psychiatry 53: 1096-1098 (1990).
53. 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. Neurodegener Dis 7: 373-378 (2010).
54. Mulder C, Schoonenboom NS, Jansen EE, Verhoeven NM, van Kamp GJ, Jakobs C, et al. The transmethylation cycle in the brain of Alzheimer patients. Neurosci Lett 386: 69-71 (2005).
55. Gomes Trolin C, Regland B, Oreland L. Decreased methionine adenosyltransferase activity in erythrocytes of patients with dementia disorders. Eur Neuropsychopharmacol 5: 107-114 (1995).
56. Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K, Widner B, Reibnegger G, et al. Hyperhomocysteinemia in dementia. J Neural Transm 107: 1469-1474 (2000).
57. Malaguarnera M, Ferri R, Bella R, Alagona G, Carnemolla A, Pennisi G. Homocysteine, vitamin B12 and folate in vascular dementia and in Alzheimer disease. Clin Chem Lab Med 42: 1032-1035 (2004).
58. Joosten E, Lesaffre E, Riezler R, Ghekiere V, Dereymaeker L, Pelemans W, et al. Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease? J Gerontol A Biol Sci Med Sci 52: M76-M79 (1997).
59. Agnati LF, Genedani S, Rasio G, Galantucci M, Saltini S, Filaferro M, et al. Studies on homocysteine plasma levels in Alzheimer's patients. Relevance for neurodegeneration. J Neural Transm 112: 163-169 (2005).
60. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346: 476-483 (2002).
61. Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr 80: 114-122 (2004).
62. Selley ML, Close DR, Stern SE. The effect of increased concentrations of homocysteine on the concentration of (E)-4-hydroxy-2- nonenal in the plasma and cerebrospinal fluid of patients with Alzheimer's disease. Neurobiol Aging 23: 383-388 (2002).
63. Li L, Cao D, Desmond R, Rahman A, Lah JJ, Levey AI, et al. Cognitive performance and plasma levels of homocysteine, vitamin B12, folate and lipids in patients with Alzheimer disease. Dement Geriatr Cogn Disord 26: 384-390 (2008).
64. Cazzaniga E, Bulbarelli A, Lonati E, Re F, Galimberti G, Gatti E, et al. Enhanced folate binding of cultured fibroblasts from Alzheimer's disease patients. Neurosci Lett 436: 317-320 (2008).
65. Kim JM, Stewart R, Kim SW, Shin IS, Yang SJ, Shin HY, et al. Changes in folate, vitamin B12 and homocysteine associated with incident dementia. J Neurol Neurosurg Psychiatry 79: 864-868 (2008).
66. Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Int J Geriatr Psychiatry 16: 609-614 (2001).
67. Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol 64: 86-92 (2007).
68. Kado DM, Karlamangla AS, Huang MH, Troen A, Rowe JW, Selhub J, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older highfunctioning adults: MacArthur Studies of Successful Aging. Am J Med 118: 161-167 (2005).
69. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA 300: 1774-1783 (2008).
70. Fuso A, Nicolia V, Cavallaro RA, Scarpa S. DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer's disease models. J Nutr Biochem 22: 242-251 (2011).
71. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 28: 1057-1068 (2010).
72. Rahman A. The role of adenosine in Alzheimer's disease. Curr Neuropharmacol 7: 207-216 (2009).
73. Albasanz JL, Perez S, Barrachina M, Ferrer I, Martin M. Upregulation of adenosine receptors in the frontal cortex in Alzheimer's disease. Brain Pathol 18: 211-219 (2008).
74. Buira SP, Albasanz JL, Dentesano G, Moreno J, Martin M, Ferrer I, et al. DNA methylation regulates adenosine A(2A) receptor cell surface expression levels. J Neurochem 112: 1273-1285 (2010).
75. Tohgi H, Utsugisawa K, Nagane Y, Yoshimura M, Genda Y, Ukitsu M. Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex. Brain Res Mol Brain Res 70: 288-292 (1999).
76. West RL, Lee JM, Maroun LE. Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient. J Mol Neurosci 6: 141-146 (1995).
77. Lin HC, Hsieh HM, Chen YH, Hu ML. 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 (2009).
78. Misonou H, Morishima-Kawashima M, Ihara Y. Oxidative stress induces intracellular accumulation of amyloid beta-protein (Abeta) in human neuroblastoma cells. Biochemistry 39: 6951-6959 (2000).
79. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, et al. Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9: 3-4 (2003).
80. Fuso A, Seminara L, Cavallaro RA, D'Anselmi F, Scarpa S. Sadenosylmethionine/ homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 28: 195-204 (2005).
81. Fuso A, Cavallaro RA, Zampelli A, D'Anselmi F, Piscopo P, Confaloni A, et al. Gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells. J Alzheimers Dis 11: 275-290 (2007).
82. Fuso A, Nicolia V, Cavallaro RA, Ricceri L, D'Anselmi F, Coluccia P, et al. B-vitamin deprivation induces hyperhomocysteinemia and brain S-adenosylhomocysteine, depletes brain Sadenosylmethionine, and enhances PS1 and BACE expression and amyloid-beta deposition in mice. Mol Cell Neurosci 37: 731-746 (2008).
83. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 10: 279-288 (2002).
84. Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, et al. Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem104: 683-695 (2008).
85. Quiroz-Baez R, Rojas E, Arias C. Oxidative stress promotes JNKdependent amyloidogenic processing of normally expressed human APP by differential modification of alpha-, beta- and gammasecretase expression. Neurochem Int 55: 662-670 (2009).
86. Chen L, Na R, Gu M, Richardson A, Ran Q. Lipid peroxidation upregulates BACE1 expression in vivo: a possible early event of amyloidogenesis in Alzheimer's disease. J Neurochem 107: 197-207 (2008).
87. Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, et al. Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci USA 105: 3622-3627 (2008).
88. Armentero MT, Sinforiani E, Ghezzi C, Bazzini E, Levandis G, Ambrosi G, et al. Peripheral expression of key regulatory kinases in Alzheimer's disease and Parkinson's disease. Neurobiol Aging Epub (2010).
89. Onyango IG, Bennett JP, Jr., Tuttle JB. Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids. Neurobiol Dis 19: 312-322 (2005).
90. Monaco EA, 3rd. Recent evidence regarding a role for Cdk5 dysregulation in Alzheimer's disease. Curr Alzheimer Res 1: 33-38 (2004).
91. Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW. Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 101: 2173-2178 (2004).
92. Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood 116: 1025-1034 (2010).
93. Shirvan A, Ziv I, Zilkha-Falb R, Machlyn T, Barzilai A, Melamed E. Expression of cell cycle-related genes during neuronal apoptosis: is there a distinct pattern? Neurochem Res 23: 767-777 (1998).
94. De Souza EB. Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology 20: 789-819 (1995).
95. De Souza EB, Whitehouse PJ, Kuhar MJ, Price DL, Vale WW. Reciprocal changes in corticotropin-releasing factor (CRF)-like immunoreactivity and CRF receptors in cerebral cortex of Alzheimer's disease. Nature 319: 593-595 (1986).
96. Cavallaro RA, Fuso A, D'Anselmi F, Seminara L, Scarpa S. The effect of S-adenosylmethionine on CNS gene expression studied by cDNA microarray analysis. J Alzheimers Dis 9: 415-419 (2006).
97. Vincent I, Jicha G, Rosado M, Dickson DW. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J Neurosci 17: 3588-3598 (1997).
98. Drzewinska J, Walczak-Drzewiecka A, Ratajewski M. Identification and analysis of the promoter region of the human DHCR24 gene: involvement of DNA methylation and histone acetylation. Mol Biol Rep 38: 1091-1101 (2011).
99. Iivonen S, Hiltunen M, Alafuzoff I, Mannermaa A, Kerokoski P, Puolivali J, et al. Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease. Neuroscience 113: 301-310 (2002).
100. Recuero M, Vicente MC, Martinez-Garcia A, Ramos MC, Carmona-Saez P, Sastre I, et al. A free radical-generating system induces the cholesterol biosynthesis pathway: a role in Alzheimer's disease. Aging Cell 8: 128-139 (2009).
101. Coni P, Pang J, Pichiri-Coni G, Hsu S, Rao PM, Rajalakshmi S, et al. Hypomethylation of beta-hydroxy-beta-methyl-glutaryl coenzyme A reductase gene and its expression during hepatocarcinogenesis in the rat. Carcinogenesis 13: 497-499 (1992).
102. Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol Aging 22: 837-842 (2001).
103. Nile CJ, Read RC, Akil M, Duff GW, Wilson AG. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum 58: 2686-2693 (2008).
104. Frossi B, De Carli M, Daniel KC, Rivera J, Pucillo C. Oxidative stress stimulates IL-4 and IL-6 production in mast cells by an APE/Ref-1-dependent pathway. Eur J Immunol 33:2168-2177 (2003).
105. Lee YW, Lee WH, Kim PH. Oxidative mechanisms of IL-4- induced IL-6 expression in vascular endothelium. Cytokine 49: 73-79 (2010).
106. Grammas P, Samany PG, Thirumangalakudi L. Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. J Alzheimers Dis 9: 51-58 (2006).
107. Andia DC, de Oliveira NF, Casarin RC, Casati MZ, Line SR, de Souza AP. DNA methylation status of the IL8 gene promoter in aggressive periodontitis. J Periodontol 81: 1336-1341 (2010).
108. Oliveira NF, Damm GR, Andia DC, Salmon C, Nociti FH, Jr., Line SR, et al. DNA methylation status of the IL8 gene promoter in oral cells of smokers and non-smokers with chronic periodontitis. J Clin Periodontol 36: 719-725 (2009).
109. Verhasselt V, Goldman M, Willems F. Oxidative stress upregulates IL-8 and TNF-alpha synthesis by human dendritic cells. Eur J Immunol 28: 3886-3890 (1998).
110. Yoshida H, Hastie CJ, McLauchlan H, Cohen P, Goedert M. Phosphorylation of microtubule-associated protein tau by isoforms of c- Jun N-terminal kinase (JNK). J Neurochem 90: 352-358 (2004).
111. Zhu X, Raina AK, Rottkamp CA, Aliev G, Perry G, Boux H, et al. Activation and redistribution of c-jun N-terminal kinase/stress activated protein kinase in degenerating neurons in Alzheimer's disease. J Neurochem 76: 435-441 (2001).
112. Tripathy D, Thirumangalakudi L, Grammas P. Expression of macrophage inflammatory protein 1-alpha is elevated in Alzheimer's vessels and is regulated by oxidative stress. J Alzheimers Dis 11: 447-455 (2007).
113. Mathieu-Kia AM, Fan LQ, Kreek MJ, Simon EJ, Hiller JM. Mu-, delta- and kappa-opioid receptor populations are differentially altered in distinct areas of postmortem brains of Alzheimer's disease patients. Brain Res 893: 121-134 (2001).
114. Russo R, Borghi R, Markesbery W, Tabaton M, Piccini A. Neprylisin decreases uniformly in Alzheimer's disease and in normal aging. FEBS Lett 579: 6027-6030 (2005).
115. Fisk L, Nalivaeva NN, Boyle JP, Peers CS, Turner AJ. Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes. Neurochem Res 32: 1741-1748 (2007).
116. Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel UL. Inflammation and NF-kappaB in Alzheimer's disease and diabetes. J Alzheimers Dis 16: 809-821 (2009).
117. Terai K, Matsuo A, McGeer PL. Enhancement of immunoreactivity for NF-kappa B in the hippocampal formation and cerebral cortex of Alzheimer's disease. Brain Res 735: 159-168 (1996).
118. Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer's disease. Neuropharmacology 58: 561-568 (2010).
119. Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA. Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59: 880-888 (2000).
120. Liu R, Wang JZ. Protein phosphatase 2A in Alzheimer's disease. Pathophysiology 16: 273-277 (2009).
121. Vogelsberg-Ragaglia V, Schuck T, Trojanowski JQ, Lee VM. PP2A mRNA expression is quantitatively decreased in Alzheimer's disease hippocampus. Exp Neurol 168: 402-412 (2001).
122. Sunahori K, Juang YT, Tsokos GC. Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. J Immunol 182: 1500-1508 (2009).
123. Chen L, Liu L, Yin J, Luo Y, Huang S. Hydrogen peroxide-induced euronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol 41: 1284-1295 (2009).
124. Fuso A, Nicolia V, Pasqualato A, Fiorenza MT, Cavallaro RA, Scarpa S. Changes in Presenilin 1 gene methylation pattern in dietinduced B vitamin deficiency. Neurobiol Aging. 32: 187-199 (2011).
125. Hoyaux D, Decaestecker C, Heizmann CW, Vogl T, Schafer BW, Salmon I, et al. S100 proteins in Corpora amylacea from normal human brain. Brain Res 867: 280-288 (2000).
126. Ito H, Usuda N, Atsuzawa K, Iwamoto I, Sudo K, Katoh-Semba R, et al. Phosphorylation by extracellular signal-regulated kinase of a multidomain adaptor protein, vinexin, at synapses. J Neurochem 100: 545-554 (2007).
127. Pieper HC, Evert BO, Kaut O, Riederer PF, Waha A, Wullner U. Different methylation of the TNF-alpha promoter in cortex and substantia nigra: Implications for selective neuronal vulnerability. Neurobiol Dis 32: 521-527 (2008).
128. Kitamura Y, Shimohama S, Kamoshima W, Matsuoka Y, Nomura Y, Taniguchi T. Changes of p53 in the brains of patients with Alzheimer's disease. Biochem Biophys Res Commun 232: 418-421 (1997).
129. Amatya VJ, Naumann U, Weller M, Ohgaki H. TP53 promoter methylation in human gliomas. Acta Neuropathol 110: 178-184 (2005).
130. Halliwell B. Oxidative stress and cancer: have we moved forward? Biochem J 401: 1-11 (2007).
131. Hussain AM, Mitra AK. Effect of aging on tryptophan hydroxylase in rat brain: implications on serotonin level. Drug Metab Dispos 28: 1038-1042 (2000).
132. Barrachina M, Ferrer I. DNA methylation of Alzheimer disease and auopathy-related genes in postmortem brain. J Neuropathol Exp Neurol 68: 880-891 (2009).
133. Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, et al. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6: 143-150 (2000).
134. Hureau C, Faller P. Abeta-mediated ROS production by Cu ions: Structural insights, mechanisms and relevance to Alzheimer's disease. Biochimie 91: 1212-1217 (2009).
135. Yatin SM, Varadarajan S, Butterfield DA. Vitamin E Prevents Alzheimer's Amyloid beta-Peptide (1-42)-Induced Neuronal Protein Oxidation and Reactive Oxygen Species Production. J Alzheimers Dis 2: 123-131 (2000).
136. Park SK, Prolla TA. Lessons learned from gene expression profile studies of aging and caloric restriction. Ageing Res Rev 4: 55-65 (2005).
137. Blaesse P, Airaksinen MS, Rivera C, Kaila K. Cation-chloride cotransporters and neuronal function. Neuron 61: 820-838 (2009).
138. Schilling E, Rehli M. Global, comparative analysis of tissuespecific promoter CpG methylation. Genomics 90: 314-323 (2007).
139. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H, et al. Role for DNA methylation in the control of cell type specific maspin expression. Nat Genet 31: 175-179 (2002).
140. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298-300 (1956).
141. Gil P, Farinas F, Casado A, Lopez-Fernandez E. Malondialdehyde: a possible marker of ageing. Gerontology 48: 209-214 (2002).
142. Stadtman ER. Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci 928: 22-38 (2001).
143. Haripriya D, Sangeetha P, Kanchana A, Balu M, Panneerselvam C. Modulation of age-associated oxidative DNA damage in rat brain cerebral cortex, striatum and hippocampus by L-carnitine. Exp Gerontol 40: 129-135 (2005).
144. Sasaki T, Unno K, Tahara S, Kaneko T. Age-related increase of reactive oxygen generation in the brains of mammals and birds: is reactive oxygen a signaling molecule to determine the aging process and life span? Geriatr Gerontol Int 10: S10-S24 (2010).
145. Moller P, Lohr M, Folkmann JK, Mikkelsen L, Loft S. Aging and oxidatively damaged nuclear DNA in animal organs. Free Radic Biol Med 48: 1275-1285 (2010).
146. Navarro A, Boveris A. Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson's disease. Front Aging Neurosci 2: 34 (2010).
147. Head E. Oxidative damage and cognitive dysfunction: antioxidant treatments to promote healthy brain aging. Neurochem Res 34: 670-678 (2009).
148. Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60: 759-767 (2001).
149. Wang J, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment. J Neurochem 96: 825-832 (2006).
150. Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA. Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. J Neurochem 93: 953-962 (2005).
151. Migliore L, Fontana I, Trippi F, Colognato R, Coppede F, Tognoni G, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 26: 567-573 (2005).
152. Lovell MA, Gabbita SP, Markesbery WR. Increased DNA oxidation and decreased levels of repair products in Alzheimer's disease ventricular CSF. J Neurochem 72: 771-776 (1999).
153. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL. Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24: 2533-2545 (2010).
154. Ballatori N, Krance SM, Notenboom S, Shi S, Tieu K, Hammond CL. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem 390: 191-214 (2009).
155. Ansari MA, Scheff SW. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 69: 155-167 (2010).
156. Cavallaro RA, Fuso A, Nicolia V, Scarpa S. S-adenosylmethionine prevents oxidative stress and modulates glutathione metabolism in TgCRND8 mice fed a B-vitamin deficient diet. J Alzheimers Dis 20: 997-1002 (2010).
157. Padurariu M, Ciobica A, Hritcu L, Stoica B, Bild W, Stefanescu C. Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease. Neurosci Lett 469: 6-10 (2010).
158. Coppede F, Migliore L. DNA damage and repair in Alzheimer's disease. Curr Alzheimer Res 6: 36-47 (2009).
159. Shao C, Xiong S, Li GM, Gu L, Mao G, Markesbery WR, et al. Altered 8-oxoguanine glycosylase in mild cognitive impairment and late-stage Alzheimer's disease brain. Free Radic Biol Med 45: 813-819 (2008).
160. Iida T, Furuta A, Nishioka K, Nakabeppu Y, Iwaki T. Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain. Acta Neuropathol 103: 20-25 (2002).
161. Weissman L, Jo DG, Sorensen MM, de Souza-Pinto NC, Markesbery WR, Mattson MP, et al. Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res 35: 5545-5555 (2007).
162. Mehan S, Meena H, Sharma D, Sankhla R. JNK: A Stress- Activated Protein Kinase Therapeutic Strategies and Involvement in Alzheimer's and Various Neurodegenerative Abnormalities. J Mol Neurosci 43: 376-390 (2011).
163. Jo DG, Arumugam TV, Woo HN, Park JS, Tang SC, Mughal M, et al. Evidence that gamma-secretase mediates oxidative stressinduced beta-secretase expression in Alzheimer's disease. Neurobiol Aging 31: 917-925 (2010).
164. Pogribny IP, Beland FA. DNA hypomethylation in the origin and pathogenesis of human diseases. Cell Mol Life Sci 66: 2249-2261 (2009).
165. Alvarez H, Opalinska J, Zhou L, Sohal D, Fazzari MJ, Yu Y, et al. Widespread Hypomethylation Occurs Early and Synergizes with Gene Amplification during Esophageal Carcinogenesis. PLoS Genet 7: e1001356 (2011).
166. Matsumoto L, Takuma H, Tamaoka A, Kurisaki H, Date H, Tsuji S, et al. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease. PLoS One 5: e15522 (2010).
167. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49: 1603-1616 (2010).
168. Rasanen JV, Sihvo EI, Ahotupa MO, Farkkila MA, Salo JA. The expression of 8-hydroxydeoxyguanosine in oesophageal tissues and tumours. Eur J Surg Oncol 33: 1164-1168 (2007).
169. Tunc O, Tremellen K. Oxidative DNA damage impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet 26: 537-544 (2009).
170. Bhusari SS, Dobosy JR, Fu V, Almassi N, Oberley T, Jarrard DF. Superoxide dismutase 1 knockdown induces oxidative stress and DNA methylation loss in the prostate. Epigenetics 5: 402-409 (2010).
171. Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, et al. Oxidative imbalance in patients with mild cognitive impairment and Alzheimer's disease. Neurobiol Aging 27: 262-269 (2006).
172. Bagnyukova TV, Powell CL, Pavliv O, Tryndyak VP, Pogribny IP. Induction of oxidative stress and DNA damage in rat brain by a folate/ methyl-deficient diet. Brain Res 1237: 44-51 (2008).
173. Ooi SK, Bestor TH. The colorful history of active DNA demethylation. Cell 133: 1145-1148 (2008).
174. Zhu JK. Active DNA demethylation mediated by DNA glycosylases. Annu Rev Genet 43: 143-166 (2009).
175. Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Cairns BR. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell 135: 1201-1212 (2008).
176. Torp R, Su JH, Deng G, Cotman CW. GADD45 is induced in Alzheimer's disease, and protects against apoptosis in vitro. Neurobiol Dis 5: 245-252 (1998).
177. Weitzman SA, Turk PW, Milkowski DH, Kozlowski K. Free radical adducts induce alterations in DNA cytosine methylation. Proc Natl Acad Sci USA 91: 1261-1264 (1994).
178. Turk PW, Laayoun A, Smith SS, Weitzman SA. DNA adduct 8- hydroxyl-2'-deoxyguanosine (8-hydroxyguanine) affects function of human DNA methyltransferase. Carcinogenesis 16: 1253-1255 (1995).
179. Valinluck V, Sowers LC. Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Res 67: 946-950 (2007).
180. Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC. Oxidative damage to methyl-CpG sequences inhibits the bind ing of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res 32: 4100-4108 (2004).
181. Zawia NH, Lahiri DK, Cardozo-Pelaez F. Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 46: 1241-1249 (2009).
182. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930-935 (2009).
183. Ito S, D'Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell selfrenewal and inner cell mass specification. Nature 466: 1129-1133 (2010).
184. Ficz G, Branco MR, Seisenberger S, Santos F, Krueger F, Hore TA, et al. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473 (7347): 398-402 (2011).
185. Jin SG, Wu X, Li AX, Pfeifer GP. Genomic mapping of 5- hydroxymethylcytosine in the human brain. Nucleic Acids Res 39(12): 5015-5024 (2011).
186. Wu H, D'Alessio AC, Ito S, Xia K, Wang Z, Cui K, et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473 (7347): 389-393 (2011).
187. Privat E, Sowers LC. Photochemical deamination and demethylation of 5-methylcytosine. Chem Res Toxicol 9: 745-750 (1996).
188. Rusmintratip V, Sowers LC. An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts. Proc Natl Acad Sci USA 97: 14183-14187 (2000).
189. Kriaucionis S, Heintz N. The nuclear DNA base 5- hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324: 929-930 (2009).
190. Demple B, Harrison L. Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem 63: 915-948 (1994).
191. Huang JC, Svoboda DL, Reardon JT, Sancar A. Human nucleotide excision nuclease removes thymine dimers from DNA by incising the 22nd phosphodiester bond 5' and the 6th phosphodiester bond 3' to the photodimer. Proc Natl Acad Sci USA 89: 3664-3668 (1992).
192. Martin LJ. DNA damage and repair: relevance to mechanisms of neurodegeneration. J Neuropathol Exp Neurol 67: 377-387 (2008).
193. Nouspikel T. Nucleotide excision repair and neurological diseases. DNA Repair (Amst) 7: 1155-11567 (2008).
194. McMurray CT. To die or not to die: DNA repair in neurons. Mutat Res 577: 260-274 (2005).
195. Gorbunova V, Seluanov A, Mao Z, Hine C. Changes in DNA repair during aging. Nucleic Acids Res 35: 7466-7474 (2007).
196. Goukassian D, Gad F, Yaar M, Eller MS, Nehal US, Gilchrest BA. Mechanisms and implications of the age-associated decrease in DNA repair capacity. FASEB J 14: 1325-1334 (2000).
197. Reardon JT, Bessho T, Kung HC, Bolton PH, Sancar A. In vitro repair of oxidative DNA damage by human nucleotide excision repair system: possible explanation for neurodegeneration in xeroderma pigmentosum patients. Proc Natl Acad Sci USA 94: 9463-9468 (1997).
198. Kassam SN, Rainbow AJ. Deficient base excision repair of oxidative DNA damage induced by methylene blue plus visible light in xeroderma pigmentosum group C fibroblasts. Biochem Biophys Res Commun 359: 1004-1009 (2007).
199. Miao F, Bouziane M, Dammann R, Masutani C, Hanaoka F, Pfeifer G, et al. 3-Methyladenine-DNA glycosylase (MPG protein) interacts with human RAD23 proteins. J Biol Chem 275: 28433-28438 (2000).
200. D'Errico M, Parlanti E, Teson M, Degan P, Lemma T, Calcagnile A, et al. The role of CSA in the response to oxidative DNA damage in human cells. Oncogene 26: 4336-4343 (2007).
201. Tuo J, Jaruga P, Rodriguez H, Bohr VA, Dizdaroglu M. Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress. FASEB J 17: 668-674 (2003).
202. Wong HK, Muftuoglu M, Beck G, Imam SZ, Bohr VA, Wilson DM, 3rd. Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates. Nucleic Acids Res 35: 4103-4113 (2003).
203. Trapp C, Reite K, Klungland A, Epe B. Deficiency of the Cockayne syndrome B (CSB) gene aggravates the genomic instability caused by endogenous oxidative DNA base damage in mice. Oncogene 26: 4044-4048 (2007).
204. Pastoriza-Gallego M, Armier J, Sarasin A. Transcription through 8- oxoguanine in DNA repair-proficient and Csb(-)/Ogg1(-) DNA repair-deficient mouse embryonic fibroblasts is dependent upon promoter strength and sequence context. Mutagenesis 22: 343-351(2007).
205. Barreto G, Schafer A, Marhold J, Stach D, Swaminathan SK, Handa V, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445: 671-675 (2007).
206. Le May N, Mota-Fernandes D, Velez-Cruz R, Iltis I, Biard D, Egly JM. NER factors are recruited to active promoters and facilitate chromatin modification for transcription in the absence of exogenous genotoxic attack. Mol Cell 38: 54-66 (2010).
207. Schmitz KM, Schmitt N, Hoffmann-Rohrer U, Schafer A, Grummt I, Mayer C. TAF12 recruits Gadd45a and the nucleotide excision repair complex to the promoter of rRNA genes leading to active DNA demethylation. Mol Cell 13; 33: 344-353 (2009).
208. Koturbash I, Pogribny I, Kovalchuk O. Stable loss of global DNA methylation in the radiation-target tissue--a possible mechanism contributing to radiation carcinogenesis? Biochem Biophys Res Commun 337: 526-533 (2005).
209. Adamec E, Vonsattel JP, Nixon RA. DNA strand breaks in Alzheimer's disease. Brain Res 849: 67-77 (1999).
210. Rao KS. Genomic damage and its repair in young and aging brain. Mol Neurobiol 7: 23-48 (1993).
211. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3: 601-614 (2003).
212. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr 130: 129-132 (2000).
213. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, et al. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci 22: 1752-1762 (2002).
214. Caldecott KW. Mammalian DNA single-strand break repair: an Xra(y)ted affair. Bioessays 23: 447-455 (2001).
215. Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463: 191-196 (2010).
216. Dahl C, Gronbaek K, Guldberg P. Advances in DNA methylation: 5-hydroxymethylcytosine revisited. Clin Chim Acta 412: 831-836 (2011).
217. Rafii MS, Aisen PS. Recent developments in Alzheimer's diseasetherapeutics. BMC Med 19: 7 (2009).
218. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336: 1216-1222 (1997).
219. Brewer GJ. Why vitamin E therapy fails for treatment of Alzheimer's disease. J Alzheimers Dis 19: 27-30 (2010).
220. Lahiri DK, Maloney B, Zawia NH (2009) The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 14: 992-1003 (2009).