[Frontiers In Bioscience, Landmark, 23, 1113-1143, January 1, 2018]

Choline, the brain and neurodegeneration: insights from epigenetics

Rola A. Bekdash1

1Department of Biological Sciences, Rutgers University, Newark, NJ 07102

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Epigenetic mechanisms and neurodegeneration
3.1. DNA methylation
3.2. Histone Posttranslational modifications
3.3. Non-coding RNAs
3.4. Choline as an epigenetic modulator of the genome
4. Choline physiological functions
5. Cholinergic neurotransmission, membrane integrity and neurodegeneration
6. Potential neuroprotective effects of choline
6.1. Choline and the developing brain
6.2. Choline and the aging brain
7. Conclusion
8. References

1. ABSTRACT

Neurodegenerative disorders are a major public health problem worldwide with huge socioeconomic effect. Recent evidence suggests that neurodegeneration is not only caused by genetic factors but also affected by environmental factors including nutrients. Environmental influences have been shown to cause epigenetic modifications in the brain with long-lasting effects on behavior if they occur in early life. It has been suggested that early nutritional intervention that includes choline, betaine, VitB6, VitB12 and/or folic acid could attenuate decline in cognitive functions. Recently, choline emerged as an essential micronutrient for normal brain development and an epigenetic modifier of the genome that could alter neuronal gene methylation, expression and activity. Choline maintains the structural and functional integrity of membranes and regulates cholinergic neurotransmission via the synthesis of acetylcholine. Choline-related functions have been shown to be dysregulated in several neurodegenerative disorders suggesting a potential role of nutrients in mental health. We will discuss the role of epigenetic mechanisms in neurodegeneration and how nutrients could interact with the epigenome to protect or boost cognitive processes across the lifespan.

8. REFERENCES

1. R.L. Jirtle, M.K. Skinner: Environmental epigenomics and disease susceptibility. Nat Rev Genet 8(4), 253–62 (2007)
DOI: 10.1038/nrg2045

2. S.E. Sillivan, T. Vaissière, C.A. Miller: Neuroepigenetic Regulation of Pathogenic Memories. Neuroepigenetics 1, 28–33 (2015)
DOI: 10.1016/j.nepig.2014.10.003

3. V.F. Prado, H. Janickova, M.A. Al-Onaizi, M.A.M. Prado: Cholinergic circuits in cognitive flexibility. Neuroscience (2016)

4. S.K., Tayebati, F. Amenta: Choline-containing phospholipids: relevance to brain functional pathways. Clin Chem Lab Med 51(3), 513–21 (2013)

5. P. Fagone, S. Jackowski: Phosphatidylcholine and the CDP-choline cycle. Biochim Biophys Acta 1831(3), 523–32 (2013)
DOI: 10.1016/j.bbalip.2012.09.009

6. T.H. Ferreira-Vieira, I.M. Guimaraes, F.R. Silva, F.M. Ribeiro: Alzheimer’s disease: Targeting the Cholinergic System. Curr Neuropharmacol 14(1), 101–15 (2016)
DOI: 10.2174/1570159X13666150716165726

7. L. Whiley, A. Sen, J. Heaton, P. Proitsi, D. García-Gómez, R. Leung et al: Evidence of altered phosphatidylcholine metabolism in Alzheimer’s disease. Neurobiol Aging 35(2), 271–8 (2014)
DOI: 10.1016/j.neurobiolaging.2013.08.001

8. J. Klein: Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J Neural Transm Vienna Austria 107(8-9), 1027–63 (1996)
DOI: 10.1007/s007020070051

9. J.K., Blusztajn, T.J. Mellott: Choline nutrition programs brain development via DNA and histone methylation. Cent Nerv Syst Agents Med Chem 12(2), 82–94 (2012)
DOI: 10.2174/187152412800792706

10. S.H. Zeisel: Choline: needed for normal development of memory. J Am Coll Nutr 19(5 Suppl), 528S – 531S (2000)
DOI: 10.1080/07315724.2000.10718976

11. K.M. Schulz, J.N. Pearson, M.E. Gasparrini, K.F. Brooks, C. Drake-Frazier, M.E. Zajkowski, et al: Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors. Behav Brain Res 268,104–10 (2014)
DOI: 10.1016/j.bbr.2014.03.031

12. W.H. Meck, C.L., Williams, J.M. Cermak, J.K. Blusztajn: Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci 1:7 (2007)

13. W.H. Meck, C.L. Williams: Perinatal choline supplementation increases the threshold for chunking in spatial memory. Neuroreport 8(14), 3053–9 (1997)
DOI: 10.1097/00001756-199709290-00010

14. W.H. Meck, C.L. Williams: Choline supplementation during prenatal development reduces proactive interference in spatial memory. Brain Res Dev Brain Res 118(1-2), 51–9 (1999)
DOI: 10.1016/S0165-3806(99)00105-4

15. R.G. Ross, S.K. Hunter, L. McCarthy, J. Beuler, A.K. Hutchison, B.D. Wagner, et al: Perinatal Choline Effects on Neonatal Pathophysiology Related to Later Schizophrenia Risk. Am J Psychiatry 170(3), 290–8 (2013)
DOI: 10.1176/appi.ajp.2012.12070940

16. R.G. Ross, K.E. Stevens, W.R. Proctor, S. Leonard, M.A. Kisley, S.K. Hunter, et al: Research review: Cholinergic mechanisms, early brain development, and risk for schizophrenia. J Child Psychol Psychiatry 51(5), 535–49 (2010)
DOI: 10.1111/j.1469-7610.2009.02187.x

17. J. Moon, M. Chen, S.U. Gandhy, M. Strawderman, D.A. Levitsky, K.N. Maclean, et al: Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. Behav Neurosci 124(3), 346–61 (2010)
DOI: 10.1037/a0019590

18. R.H. Wu, T. O’Donnell, M. Ulrich, S.J. Asghar, C.C. Hanstock, P.H. Silverstone: Brain choline concentrations may not be altered in euthymic bipolar disorder patients chronically treated with either lithium or sodium valproate. Ann Gen Psychiatry 3(1), 13 (2004).
DOI: 10.1186/1475-2832-3-13

19. N. Nag, T.J. Mellott, J.E. Berger-Sweeney: Effects of postnatal dietary choline supplementation on motor regional brain volume and growth factor expression in a mouse model of Rett syndrome. Brain Res 1237, 101–9 (2008)
DOI: 10.1016/j.brainres.2008.08.042

20. B.C. Ward, N.H. Kolodny, N. Nag, J.E. Berger-Sweeney: Neurochemical changes in a mouse model of Rett syndrome: changes over time and in response to perinatal choline nutritional supplementation. J Neurochem 108(2), 361–71 (2009)
DOI: 10.1111/j.1471-4159.2008.05768.x

21. N. Nag, J.E. Berger-Sweeney: Postnatal dietary choline supplementation alters behavior in a mouse model of Rett syndrome. Neurobiol Dis 26(2), 473–80 (2007)
DOI: 10.1016/j.nbd.2007.02.003

22. B.J. Strupp, B.E. Powers, R. Velazquez, J.A. Ash, C.M. Kelley, M.J. Alldred, et al: Maternal Choline Supplementation: A Potential Prenatal Treatment for Down Syndrome and Alzheimer’s Disease. Curr Alzheimer Res 13(1), 97–106 (2016)
DOI: 10.2174/1567205012666150921100311

23. Y. Yang, Z. Liu, J.M. Cermak, P. Tandon, M.R. Sarkisian, C.E. Stafstrom, et al: Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci 20(22), RC109 (2000)

24. G.L. Holmes, Y. Yang, Z. Liu, J.M. Cermak, M.R. Sarkisian, C.E. Stafstrom, et al: Seizure-induced memory impairment is reduced by choline supplementation before or after status epilepticus. Epilepsy Res 48(1-2), 3–13 (2002)
DOI: 10.1016/S0920-1211(01)00321-7

25. S.J.E. Wong-Goodrich, M.J. Glenn, T.J. Mellott, Y.B. Liu, J.K. Blusztajn, C.L. Williams: Water maze experience and prenatal choline supplementation differentially promote long-term hippocampal recovery from seizures in adulthood. Hippocampus 21(6), 584–608 (2011)
DOI: 10.1002/hipo.20783

26. B. Gómez-Ansón, M. Alegret, E. Muñoz, A. Sainz, G.C. Monte, E. Tolosa: Decreased frontal choline and neuropsychological performance in preclinical Huntington disease. Neurology 68(12), 906–10 (2007)
DOI: 10.1212/01.wnl.0000257090.01107.2f

27. J. Cummings, P. Scheltens, I. McKeith, R. Blesa, J.E. Harrison, P.H.F. Bertolucci, et al: Effect Size Analyses of Souvenaid in Patients with Alzheimer’s Disease. J Alzheimers Dis JAD 55(3), 1131–9 (2017)
DOI: 10.3233/JAD-160745

28. E.T.M. Leermakers, E.M. Moreira, J.C. Kiefte-de Jong, S.K.L. Darweesh, T. Visser, T. Voortman, et al: Effects of choline on health across the life course: a systematic review. Nutr Rev 73(8), 500–22 (2015)
DOI: 10.1093/nutrit/nuv010

29. N. van Wijk, L.M. Broersen, M.C. de Wilde, R.J.J. Hageman, M. Groenendijk, J.W.C. Sijben, et al: Targeting synaptic dysfunction in Alzheimer’s disease by administering a specific nutrient combination. J Alzheimers Dis 38(3), 459–79 (2014)

30. E.J. Nestler: Epigenetic mechanisms of drug addiction. Neuropharmacology 76 Pt B, 259–68 (2014)

31. J. Mill, T. Tang, Z. Kaminsky, T. Khare, S. Yazdanpanah, L. Bouchard, et al: Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82(3), 696–711 (2008)
DOI: 10.1016/j.ajhg.2008.01.008

32. R.G. Hunter: Epigenetic effects of stress and corticosteroids in the brain. Front Cell Neurosci 6, 18 (2012)
DOI: 10.3389/fncel.2012.00018

33. T. Klengel, J. Pape, E.B. Binder, D. Mehta: The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology 80, 115–32 (2014)
DOI: 10.1016/j.neuropharm.2014.01.013

34. D. Mastroeni, A. Grover, E. Delvaux, C. Whiteside, P.D. Coleman, J. Rogers: Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging 31(12), 2025–37 (2010)
DOI: 10.1016/j.neurobiolaging.2008.12.005

35. N.H. Zawia, D.K. Lahiri, F. Cardozo-Pelaez: Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 46(9), 1241–9 (2009)
DOI: 10.1016/j.freeradbiomed.2009.02.006

36. N.H. Myung, X. Zhu, I.I. Kruman, R.J. Castellani, R.B. Petersen, S.L. Siedlak, et al: Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes. Age Dordr Neth 30(4), 209–15 (2008)
DOI: 10.1007/s11357-008-9050-7

37. R. Holliday: Epigenetics comes of age in the twentyfirst century. J Genet 81(1), 1–4 (2002)
DOI: 10.1007/BF02715863

38. D. Haig: The (dual) origin of epigenetics. Cold Spring Harb Symp Quant Biol 69, 67–70 (2004)
DOI: 10.1101/sqb.2004.69.67

39. L. Liu, Y. Li, T.O. Tollefsbol: Gene-environment interactions and epigenetic basis of human diseases. Curr Issues Mol Biol 10(1-2), 25–36 (2008)

40. S.A. Tammen, S. Friso, S.W. Choi: Epigenetics: the link between nature and nurture. Mol Aspects Med 34(4), 753–64 (2013)
DOI: 10.1016/j.mam.2012.07.018

41. Y. Jiang, B. Langley, F.D. Lubin, W. Renthal, M.A. Wood, D.H. Yasui, et al: Epigenetics in the Nervous System. J Neurosci 28(46), 11753–9 (2008)
DOI: 10.1523/JNEUROSCI.3797-08.2008

42. R. Jaenisch, A. Bird: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl, 245–54 (2003)

43. K.D. Robertson, A.P. Wolffe: DNA methylation in health and disease. Nat Rev Genet 1(1), 11–9 (2002)
DOI: 10.1038/35049533

44. N. Coppieters, M. Dragunow: Epigenetics in Alzheimer’s disease: a focus on DNA modifications. Curr Pharm Des 17(31), 3398–412 (2011)
DOI: 10.2174/138161211798072544

45. S. Friso, S. Udali, D. De Santis, S. W. Choi: One-carbon metabolism and epigenetics. Mol Aspects Med 54, 28-36 (2017)
DOI: 10.1016/j.mam.2016.11.007

46. A.P. Bird, A.P. Wolffe: Methylation-induced repression--belts, braces, and chromatin. Cell 99(5), 451–4 (1999)
DOI: 10.1016/S0092-8674(00)81532-9

47. A. Hermann, H. Gowher, A. Jeltsch: Biochemistry and biology of mammalian DNA methyltransferases. Cell Mol Life Sci 61(19-20), 2571–87 (2004)
DOI: 10.1007/s00018-004-4201-1

48. Z. Chen, A.D. Riggs: DNA methylation and demethylation in mammals. J Biol Chem 286(21), 18347–53 (2011)
DOI: 10.1074/jbc.R110.205286

49. S.K.T. Ooi, C. Qiu, E. Bernstein, K. Li, D. Jia, Z. Yang, et al: DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448(7154), 714–7 (2007)
DOI: 10.1038/nature05987

50. M.G. Goll, F. Kirpekar, K.A. Maggert, J.A. Yoder, C.L. Hsieh, X. Zhang, et al: Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311(5759),395–8 (2006)
DOI: 10.1126/science.1120976

51. M.G. Mehedint, M.D. Niculescu, C.N. Craciunescu, S.H. Zeisel: Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the calbindin 1 gene. FASEB J 24(1):184–95 (2010)
DOI: 10.1096/fj.09-140145

52. S.H. Zeisel: Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones. Mutat Res 733(1-2), 34–8 (2012)
DOI: 10.1016/j.mrfmmm.2011.10.008

53. M.D. Niculescu, C.N. Craciunescu, S.H. Zeisel: Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains. FASEB J 20(1):43–9 (2006)
DOI: 10.1096/fj.05-4707com

54. S.H. Zeisel: Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones. Mutat Res 733(1-2), 34–8 (2012)
DOI: 10.1016/j.mrfmmm.2011.10.008

55. A. Jeltsch: Beyond Watson and Crick: DNA methylation and molecular enzymology of DNA methyltransferases. Chembiochem Eur J Chem Biol 3(4), 274–93 (2002)
DOI: 10.1002/1439-7633(20020402)3:4<274::AID-CBIC274>3.0.CO;2-S

56. R.J. Klose, A.P. Bird: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2), 89–97 (2006)
DOI: 10.1016/j.tibs.2005.12.008

57. R.J. Klose, A.P. Bird: Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2), 89–97 (2006)
DOI: 10.1016/j.tibs.2005.12.008

58. J.M. Levenson: DNA (cytosine-5) methyltransferase inhibitors: a potential therapeutic agent for schizophrenia. Mol Pharmacol 71(3):635–7 (2007)
DOI: 10.1124/mol.106.033266

59. C.A. Miller, J.D. Sweatt: Covalent modification of DNA regulates memory formation. Neuron 53(6), 857–69 (2007)
DOI: 10.1016/j.neuron.2007.02.022

60. J.P. Meadows, M.C. Guzman-Karlsson, S. Phillips, C. Holleman, J.L. Posey, J.J. Day, et al: DNA methylation regulates neuronal glutamatergic synaptic scaling. Sci Signal 8(382), ra61 (2015)
DOI: 10.1126/scisignal.aab0715

61. E.D. Nelson, E.T. Kavalali, L.M. Monteggia: Activity-dependent suppression of miniature neurotransmission through the regulation of DNA methylation. J Neurosci 28(2), 395–406 (2008)
DOI: 10.1523/JNEUROSCI.3796-07.2008

62. S. Ito, L. Shen, Q. Dai, S.C. Wu, L.B. Collins, J.A. Swenberg, et al: Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333(6047), 1300–3 (2011)
DOI: 10.1126/science.1210597

63. H. Chen, S. Dzitoyeva, H. Manev: Effect of aging on 5-hydroxymethylcytosine in the mouse hippocampus. Restor Neurol Neurosci 30(3), 237–45 (2012)

64. I.B. Van den Veyver, H.Y. Zoghbi: Mutations in the gene encoding methyl-CpG-binding protein 2 cause Rett syndrome. Brain Dev Suppl 1, S147–51 (2001)
DOI: 10.1016/S0387-7604(01)00376-X

65. S. C. Wang, B. Oelze, A. Schumacher: Age-specific epigenetic drift in late-onset alzheimer’s disease. PloS One 3(7), e2698 (2008)
DOI: 10.1371/journal.pone.0002698

66. F. Coppedè, M. Mancuso, G. Siciliano, L. Migliore, L. Murri: Genes and the environment in neurodegeneration. Biosci Rep 26(5), 341–67 (2006)
DOI: 10.1007/s10540-006-9028-6

67. G.L. Wenk: Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64 Suppl 9, 7–10 (2003)

68. R.L. West, J.M. Lee, L.E. Maroun: Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J Mol Neurosci 6(2), 141–6 (1995)
DOI: 10.1007/BF02736773

69. C. Lebel, F.P. MacMaster, D. Dewey: Brain metabolite levels and language abilities in preschool children. Brain Behav 6(10), e00547 (2016)
DOI: 10.1002/brb3.547

70. B.P. Kennedy, T. Bottiglieri, E. Arning, M.G. Ziegler, L.A. Hansen, E. Masliah: Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function. J Neural Transm 111(4), 547–67 (2004)
DOI: 10.1007/s00702-003-0096-5

71. D. Mastroeni, A. Grover, E. Delvaux, C. Whiteside, P.D. Coleman, J. Rogers: Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging 31(12), 025–37 (2010)
DOI: 10.1016/j.neurobiolaging.2008.12.005

72. A. Chan, J. Paskavitz, R. Remington, S. Rasmussen, T.B. Shea: Efficacy of a vitamin/nutriceutical formulation for early-stage Alzheimer’s disease: a 1-year, open-label pilot study with an 16-month caregiver extension. Am J Alzheimers Dis Other Demen 23(6), 571–85 (2008)
DOI: 10.1177/1533317508325093

73. R. Remington, A. Chan, J. Paskavitz, T.B. Shea: Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer’s disease: a placebo-controlled pilot study. Am J Alzheimers Dis Other Demen 24(1), 27–33 (2009)
DOI: 10.1177/1533317508325094

74. K.A. Jellinger: Formation and development of Lewy pathology: a critical update. J Neurol 256 Suppl 3,270–9 (2009)
DOI: 10.1007/s00415-009-5243-y

75. Y. Feng, J. Jankovic, Y.C. Wu: Epigenetic mechanisms in Parkinson’s disease. J Neurol Sci 349(1–2), 3–9 (2015)
DOI: 10.1016/j.jns.2014.12.017

76. W. Duan, B. Ladenheim, R.G. Cutler, I.I. Kruman, J.L. Cadet, M.P. Mattson: Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson’s disease. J Neurochem 80(1), 101–10 (2002)
DOI: 10.1046/j.0022-3042.2001.00676.x

77. A. Jowaed, I. Schmitt, O. Kaut, U. Wüllner: Methylation regulates alpha-synuclein expression and is decreased in Parkinson’s disease patients’ brains. J Neurosci 30(18), 6355–9 (2010)
DOI: 10.1523/JNEUROSCI.6119-09.2010

78. P. Desplats, B. Spencer, E. Coffee, P. Patel, S. Michael, C. Patrick, et al: Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases. J Biol Chem 286(11), 9031–7 (2011)
DOI: 10.1074/jbc.C110.212589

79. T. Jenuwein, C.D. Allis: Translating the histone code. Science 293(5532), 1074–80 (2001)
DOI: 10.1126/science.1063127

80. B.D. Strahl, C.D. Allis: The language of covalent histone modifications. Nature 403(6765), 41–5 (2000)
DOI: 10.1038/47412

81. J. Feng, S. Fouse, G. Fan: Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res 61(5 Pt 2), 58R – 63R (2007)
DOI: 10.1203/pdr.0b013e3180457635

82. A. Bird: Molecular biology. Methylation talk between histones and DNA. Science 294(5549), 2113–5 (2001)
DOI: 10.1126/science.1066726

83. T. Kouzarides: Chromatin modifications and their function. Cell 128(4), 693–705 (2007)
DOI: 10.1016/j.cell.2007.02.005

84. A.J. Bannister, T. Kouzarides: Regulation of chromatin by histone modifications. Cell Res 21(3), 381–95 (2011)
DOI: 10.1038/cr.2011.22

85. Y. Zhang, D. Reinberg: Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15(18), 2343–60 (2001)
DOI: 10.1101/gad.927301

86. S. L. Berger: The complex language of chromatin regulation during transcription. Nature 447(7143), 407–12 (2007)
DOI: 10.1038/nature05915

87. A. Eberharter, P.B. Becker: Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep 3(3), 224–9 (2002)
DOI: 10.1093/embo-reports/kvf053

88. L. Verdone, M. Caserta, E. Di Mauro: Role of histone acetylation in the control of gene expression. Biochem Cell Biol Biochim Biol Cell 83(3), 344–53 (2005)
DOI: 10.1139/o05-041

89. G. Orphanides, D. Reinberg: RNA polymerase II elongation through chromatin. Nature 407(6803), 471–5 (2000)
DOI: 10.1038/35035000

90. P.D. Gregory, K. Wagner, W. Hörz: Histone acetylation and chromatin remodeling. Exp Cell Res 265(2), 195–202 (2001)
DOI: 10.1006/excr.2001.5187

91. T. Jenuwein, C.D. Allis: Translating the histone code. Science 293(5532), 1074–80 (2001)
DOI: 10.1126/science.1063127

92. H. Ding, P.J. Dolan, G.V.W. Johnson: Histone deacetylase 6 interacts with the microtubule-associated protein tau. J Neurochem 106(5), 2119–30 (2008)
DOI: 10.1111/j.1471-4159.2008.05564.x

93. O. Ogawa, X. Zhu, H.G. Lee, A. Raina, M.E. Obrenovich, R. Bowser, et al: Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol (Berl) 105(5), 524–8 (2003)

94. J. Gräff, D. Rei, J.S. Guan, W.Y. Wang, J. Seo, K.M. Hennig, et al: An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483(7388), 222–6 (2012)
DOI: 10.1038/nature10849

95. A. Ricobaraza, M. Cuadrado-Tejedor, A. Pérez-Mediavilla, D. Frechilla, J. Del Río, A. García-Osta: Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacol 34(7), 1721–32 (2009)
DOI: 10.1038/npp.2008.229

96. A. Fischer, F. Sananbenesi, X. Wang, M. Dobbin, L.H. Tsai: Recovery of learning and memory is associated with chromatin remodelling. Nature 447(7141), 178–82 (2007)
DOI: 10.1038/nature05772

97. D. Baek, J. Villén, C. Shin, F.D. Camargo, S.P. Gygi, D.P. BarTel: The impact of microRNAs on protein output. Nature 455(7209), 64–71 (2008)
DOI: 10.1038/nature07242

98. V. Ambros: The functions of animal microRNAs. Nature 431(7006), 350–5 (2004)
DOI: 10.1038/nature02871

99. A.M. Krichevsky, K.S. King, C.P. Donahue, K. Khrapko, K.S. Kosik: A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9(10), 1274–81 (2003)
DOI: 10.1261/rna.5980303

100. C. Barbato, C. Giorgi, C. Catalanotto, C. Cogoni: Thinking about RNA? MicroRNAs in the brain. Mamm Genome Off J Int Mamm Genome Soc 19(7-8), 541–51 (2008)
DOI: 10.1007/s00335-008-9129-6

101. M. Kapsimali, W.P. Kloosterman, E. de Bruijn, F. Rosa, R.H.A. Plasterk, S.W. Wilson: MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol 8(8), R173 (2007)
DOI: 10.1186/gb-2007-8-8-r173

102. G. Schratt: Fine-tuning neural gene expression with microRNAs. Curr Opin Neurobiol 19(2), 213–9 (2009)
DOI: 10.1016/j.conb.2009.05.015

103. D.P. BarTel: MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2), 281–97 (2004)
DOI: 10.1016/S0092-8674(04)00045-5

104. M.R. Fabian, N. Sonenberg, W. Filipowicz: Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79,351–79 (2010)
DOI: 10.1146/annurev-biochem-060308-103103

105. R. Hsu, C.M. Schofield, C.G. Dela Cruz, D.M. Jones-Davis, E.M. Blelloch R, Ullian: Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex. Mol Cell Neurosci 50(3-4), 283–92 (2012)
DOI: 10.1016/j.mcn.2012.06.002

106. W. Wang, E.J. Kwon, L.H. Tsai: MicroRNAs in learning, memory, and neurological diseases. Learn Mem Cold Spring Harb N 19(9), 359–68 (2012)
DOI: 10.1101/lm.026492.112

107. J.P. Cogswell, J. Ward, I.A. Taylor, M. Waters, Y. Shi, B. Cannon, et al: Identification of miRNA changes in Alzheimer’s disease brain and CSF yields putative biomarkers and insights into disease pathways. J Alzheimers Dis 14(1), 27–41 (2008)
DOI: 10.3233/JAD-2008-14103

108. E. Junn, K.W. Lee, B.S. Jeong, T.W. Chan, J.Y. Im, M.M. Mouradian: Repression of alpha-synuclein expression and toxicity by microRNA-7. Proc Natl Acad Sci U S A 106(31), 13052–7 (2009)
DOI: 10.1073/pnas.0906277106

109. N. Kanagaraj, H. Beiping, S.T. Dheen, S.S.W. Tay: Downregulation of miR-124 in MPTP-treated mouse model of Parkinson’s disease and MPP iodide-treated MN9D cells modulates the expression of the calpain/cdk5 pathway proteins. Neuroscience 272,167–79 (2014)
DOI: 10.1016/j.neuroscience.2014.04.039

110. R. Johnson, C. Zuccato, N.D. Belyaev, D.J. Guest, E. Cattaneo, N.J. Buckley: A microRNA-based gene dysregulation pathway in Huntington’s disease. Neurobiol Dis 29(3), 438–45 (2008)
DOI: 10.1016/j.nbd.2007.11.001

111. W.H. Meck, R.A. Smith, C.L. Williams: Pre- and postnatal choline supplementation produces long-term facilitation of spatial memory. Dev Psychobiol 21(4), 339–53 (1988)
DOI: 10.1002/dev.420210405

112. G.M. Shaw, S.L. Carmichael, W. Yang, S. Selvin, D.M. Schaffer: Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol 160(2), 102–9 (2004)
DOI: 10.1093/aje/kwh187

113. P.M. Arenth, K.C. Russell, J.H. Ricker, R.D. Zafonte: CDP-choline as a biological supplement during neurorecovery: a focused review. PM R (6 Suppl 1), S123–31 (2011)

114. E. Traini, V. Bramanti, F. Amenta: Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enhancing agent. Curr Alzheimer Res 10(10), 1070–9 (2013)
DOI: 10.2174/15672050113106660173

115. M.J. Glenn, E.D. Kirby, E.M. Gibson, S.J. Wong-Goodrich, T.J. Mellott, J.K. Blusztajn, et al: Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats. Brain Res 1237, 110–23 (2008)
DOI: 10.1016/j.brainres.2008.08.049

116. I. Napoli, J.K. Blusztajn, T.J. Mellott: Prenatal choline supplementation in rats increases the expression of IGF2 and its receptor IGF2R and enhances IGF2-induced acetylcholine release in hippocampus and frontal cortex. Brain Res 1237, 124–35 (2008)
DOI: 10.1016/j.brainres.2008.08.046

117. C.L. Williams, W.H. Meck, D.D. Heyer, R. Loy: Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats. Brain Res 794(2), 225–38 (1998)
DOI: 10.1016/S0006-8993(98)00229-7

118. S.H. Zeisel: A brief history of choline. Ann Nutr Metab 61(3), 254–8 (2012)
DOI: 10.1159/000343120

119. J.K. Blusztajn, R.J. Wurtman: Choline and cholinergic neurons. Science 221(4611), 614–20 (1983)
DOI: 10.1126/science.6867732

120. C. Geula, N. Nagykery, A. Nicholas, C.K. Wu: Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease. J Neuropathol Exp Neurol 67(4), 309–18 (2008)
DOI: 10.1097/NEN.0b013e31816a1df3

121. R.J. Wurtman: Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci 15(4), 117–22 (1992)
DOI: 10.1016/0166-2236(92)90351-8

122. K.A. da Costa, O.G. Kozyreva, J. Song, J.A. Galanko, L.M. Fischer, S.H. Zeisel: Common genetic polymorphisms affect the human requirement for the nutrient choline. FASEB J 20(9), 1336–44 (2006)
DOI: 10.1096/fj.06-5734com

123. L.M. Fischer, K.A. daCosta, L. Kwock, P.W. Stewart, T.S. Lu, S.P. Stabler, et al: Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr 85(5), 1275–85 (2007)

124. D.E. Vance, N.D. Ridgway: The methylation of phosphatidylethanolamine. Prog Lipid Res 27(1), 61–79 (1988)
DOI: 10.1016/0163-7827(88)90005-7

125. J.K. Blusztajn, R.J. Wurtman: Choline biosynthesis by a preparation enriched in synaptosomes from rat brain. Nature 290(5805), 417–8 (1981)
DOI: 10.1038/290417a0

126. R.J. Wurtman: Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci 15(4), 117–22 (1992)
DOI: 10.1016/0166-2236(92)90351-8

127. K.A. da Costa, C.E. Gaffney, L.M. Fischer, S.H. Zeisel: Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load. Am J Clin Nutr 81(2), 440–4 (2005)

128. K.A. da Costa, M. Badea, L.M. Fischer, S.H. Zeisel: Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. Am J Clin Nutr 80(1), 163–70 (2004)

129. K.A. da Costa, M.D. Niculescu, C.N. Craciunescu, L.M. Fischer, S.H. Zeisel: Choline deficiency increases lymphocyte apoptosis and DNA damage in humans. Am J Clin Nutr 84(1), 88–94 (2006)

130. M. Resseguie, J. Song, M.D. Niculescu, K.A. da Costa, T.A. Randall, S.H. Zeisel: Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J 21(10), 2622–32 (2007)
DOI: 10.1096/fj.07-8227com

131. E. Cho, M.D. Holmes, S.E. Hankinson, W.C. Willett: Choline and betaine intake and risk of breast cancer among post-menopausal women. Br J Cancer 102(3), 489–94 (2010)
DOI: 10.1038/sj.bjc.6605510

132. W.H. Meck, C.L. Williams: Simultaneous temporal processing is sensitive to prenatal choline availability in mature and aged rats. Neuroreport 8(14), 3045–51 (1997)
DOI: 10.1097/00001756-199709290-00009

133. L.A. Teather, R. J. Wurtman: Dietary cytidine (5’)-diphosphocholine supplementation protects against development of memory deficits in aging rats. Prog Neuropsychopharmacol Biol Psychiatry 27(4), 711–7 (2003)
DOI: 10.1016/S0278-5846(03)00086-1

134. R.M. Nitsch, J.K. Blusztajn, A.G. Pittas, B.E. Slack, J.H. Growdon, R.J. Wurtman: Evidence for a membrane defect in Alzheimer disease brain. Proc Natl Acad Sci U S A 89(5), 1671–5 (1992)
DOI: 10.1073/pnas.89.5.1671

135. V.F. Prado, H. Janickova, M.A. Al-Onaizi, M.A.M. Prado: Cholinergic circuits in cognitive flexibility. Neuroscience 345,130-141 (2016)
DOI: 10.1016/j.neuroscience.2016.09.013

136. P.J. Whitehouse, D.L. Price, R.G. Struble, A.W. Clark, J.T. Coyle, M.R. Delon: Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain. Science 215(4537), 1237–9 (1982)
DOI: 10.1126/science.7058341

137. N.J. Woolf, L.L. Butcher: Cholinergic systems mediate action from movement to higher consciousness. Behav Brain Res 221(2), 488–98 (2011)
DOI: 10.1016/j.bbr.2009.12.046

138. D.M. Armstrong, C.B. Saper, A.I. Levey, B.H. Wainer, R.D. Terry: Distribution of cholinergic neurons in rat brain: demonstrated by the immunocytochemical localization of choline acetyltransferase. J Comp Neurol 216(1), 53–68 (1983)
DOI: 10.1002/cne.902160106

139. R.P. Gaykema, G. Gaál, J. Traber, L.B. Hersh, P.G. Luiten: The basal forebrain cholinergic system: efferent and afferent connectivity and long-term effects of lesions. Acta Psychiatr Scand Suppl 366, 14–26 (1991)
DOI: 10.1111/j.1600-0447.1991.tb03105.x

140. R. Schliebs, T. Arendt: The cholinergic system in aging and neuronal degeneration. Behav Brain Res 221(2), 555–63 (2011)
DOI: 10.1016/j.bbr.2010.11.058

141. H. Marcucci, L. Paoletti, S. Jackowski, C. Banchio: Phosphatidylcholine biosynthesis during neuronal differentiation and its role in cell fate determination. J Biol Chem 285(33), 25382–93 (2010)
DOI: 10.1074/jbc.M110.139477

142. E. Posse de Chaves, D.E. Vance, R.B. Campenot, J.E. Vance: Alkylphosphocholines inhibit choline uptake and phosphatidylcholine biosynthesis in rat sympathetic neurons and impair axonal extension. Biochem J 312 (Pt 2),411–7 (1995)
DOI: 10.1042/bj3120411

143. B.M. Cohen, P.F. Renshaw, A.L. Stoll, R.J. Wurtman, D. Yurgelun-Todd, S.M. Babb: Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA 274(11), 902–7 (1995)
DOI: 10.1001/jama.274.11.902
DOI: 10.1001/jama.1995.03530110064037

144. J.K. Blusztajn: Choline, a Vital Amine. Science 281(5378), 794–5 (1998)
DOI: 10.1126/science.281.5378.794

145. J.C. McCann, M. Hudes, B.N. Ames: An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci Biobehav Rev 30(5), 696–712 (2006)
DOI: 10.1016/j.neubiorev.2005.12.003

146. W.H. Meck, C.L. Williams: Perinatal choline supplementation increases the threshold for chunking in spatial memory. Neuroreport 8(14), 3053–9 (1997)
DOI: 10.1097/00001756-199709290-00010

147. P.D. Leathwood, E. Heck, J. Mauron: Phosphatidyl choline and avoidance performance in 17 month-old SEC/1ReJ mice. Life Sci 30(13), 1065–71 (1982)
DOI: 10.1016/0024-3205(82)90526-4

148. S.L. Ladd, S.A. Sommer, S. LaBerge, W. Toscano: Effect of phosphatidylcholine on explicit memory. Clin Neuropharmacol 16(6), 540–9 (1993)
DOI: 10.1097/00002826-199312000-00007

149. S.H. Zeisel: Nutritional importance of choline for brain development. J Am Coll Nutr 23(6 Suppl), 621S – 626S (2004)
DOI: 10.1080/07315724.2004.10719433

150. L.K. Park, S. Friso, S.W. Choi: Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 71(1), 75–83 (2012)
DOI: 10.1017/S0029665111003302

151. N. Gordon: Nutrition and cognitive function. Brain Dev 19(3), 165–70 (1997)
DOI: 10.1016/S0387-7604(96)00560-8

152. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline (Internet). (cited 2015 Jan 27). Available from: http://www.nap.edu/openbook.php?record_id=6015

153. O.S. Anderson, K.E. Sant, D.C. Dolinoy: Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem 23(8), 853–9 (2012)
DOI: 10.1016/j.jnutbio.2012.03.003

154. E.A. Langley, M. Krykbaeva, J.K. Blusztajn, T.J. Mellott: High maternal choline consumption during pregnancy and nursing alleviates deficits in social interaction and improves anxiety-like behaviors in the BTBR T+Itpr3tf/J mouse model of autism. Behav Brain Res 278,210–20 (2015)
DOI: 10.1016/j.bbr.2014.09.043

155. X. Jiang, J. Yan, A.A. West, C.A. Perry, O.V. Malysheva, S. Devapatla, et al: Maternal choline intake alters the epigenetic state of fetal cortisol-regulating genes in humans. FASEB J 26(8),3563–74 (2012)
DOI: 10.1096/fj.12-207894

156. X. Jiang, A.A. West, M.A. Caudill: Maternal choline supplementation: a nutritional approach for improving offspring health? Trends Endocrinol Metab TEM 25(5), 263–73 (2014)
DOI: 10.1016/j.tem.2014.02.001

157. M.G. Mehedint, C.N. Craciunescu, S.H. Zeisel: Maternal dietary choline deficiency alters angiogenesis in fetal mouse hippocampus. Proc Natl Acad Sci U S A 107(29), 12834–9 (2010)
DOI: 10.1073/pnas.0914328107

158. M.C. Fisher, S.H. Zeisel, M.H. Mar, T.W Sadler: Perturbations in choline metabolism cause neural tube defects in mouse embryos in vitro. FASEB J Off Publ Fed Am Soc Exp Biol 16(6), 619–21 (2012)

159. S.H. Zeisel: Nutritional genomics: defining the dietary requirement and effects of choline. J Nutr 141(3), 531–4 (2011)
DOI: 10.3945/jn.110.130369

160. C.N. Craciunescu, C.D. Albright, M.H. Mar, J. Song, S.H. Zeisel: Choline availability during embryonic development alters progenitor cell mitosis in developing mouse hippocampus. J Nutr 133(11), 3614–8 (2003)

161. M.Q. Holmes-McNary, R. Loy, M.H. Mar, C.D. Albright, S.H. Zeisel: Apoptosis is induced by choline deficiency in fetal brain and in PC12 cells. Brain Res Dev Brain Res 101(1-2), 9–16 (1997)
DOI: 10.1016/S0165-3806(97)00044-8

162. W.H. Meck, C.L. Williams: Characterization of the facilitative effects of perinatal choline supplementation on timing and temporal memory. Neuroreport 8(13), 2831–5 (1997)
DOI: 10.1097/00001756-199709080-00005

163. W.H. Meck, C.L. Williams, J.M. Cermak, J.K. Blusztajn: Developmental periods of choline sensitivity provide an ontogenetic mechanism for regulating memory capacity and age-related dementia. Front Integr Neurosci 1:7 (2007)

164. W.H. Meck, R.A. Smith, C.L. Williams: Pre- and postnatal choline supplementation produces long-term facilitation of spatial memory. Dev Psychobiol 21(4), 339–53 (1988)
DOI: 10.1002/dev.420210405

165. R.C. Tees, E. Mohammadi:. The effects of neonatal choline dietary supplementation on adult spatial and configural learning and memory in rats. Dev Psychobiol 35(3), 226–40 (1999)
DOI: 10.1002/(SICI)1098-2302(199911)35:3<226::AID-DEV7>3.3.CO;2-8
DOI: 10.1002/(SICI)1098-2302(199911)35:3<226::AID-DEV7>3.0.CO;2-H

166. J.M. Davison, T.J. Mellott, V.P. Kovacheva, J.K. Blusztajn: Gestational choline supply regulates methylation of histone H3, expression of histone methyltransferases G9a (Kmt1c) and Suv39h1 (Kmt1a), and DNA methylation of their genes in rat fetal liver and brain. J Biol Chem 284(4), 1982–9 (2009)
DOI: 10.1074/jbc.M807651200

167. V.P. Kovacheva, T.J. Mellott, J.M. Davison, N. Wagner, I. Lopez-Coviella, A.C. Schnitzler, et al: Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem 282(43), 31777–88 (2007)
DOI: 10.1074/jbc.M705539200

168. Y. Zhang, D. Reinberg: Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev 15(18), 2343–60 (2001)
DOI: 10.1101/gad.927301

169. M.J. Glenn, E.M. Gibson, E.D. Kirby, T.J. Mellott, J.K. Blusztajn, C.L. Williams: Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats. Eur J Neurosci 25(8), 2473–82 (2007)
DOI: 10.1111/j.1460-9568.2007.05505.x

170. R.A. Bekdash, C. Zhang, D.K. Sarkar: Gestational choline supplementation normalized fetal alcohol-induced alterations in histone modifications, DNA methylation, and proopiomelanocortin (POMC) gene expression in β-endorphin-producing POMC neurons of the hypothalamus. Alcohol Clin Exp Res 37(7), 1133–42 (2013)
DOI: 10.1111/acer.12082

171. T.J. Mellott, M.T. Follettie, V. Diesl, A.A. Hill, I. Lopez-Coviella, J.K. Blusztajn: Prenatal choline availability modulates hippocampal and cerebral cortical gene expression. FASEB J 21(7), 1311–23 (2007)
DOI: 10.1096/fj.06-6597com

172. S.J.E. Wong-Goodrich, M.J. Glenn, T.J. Mellott, J.K. Blusztajn, W.H. Meck, C.L. Williams: Spatial memory and hippocampal plasticity are differentially sensitive to the availability of choline in adulthood as a function of choline supply in utero. Brain Res 1237, 153–66 (2008)
DOI: 10.1016/j.brainres.2008.08.074

173. C.L. Williams, W.H. Meck, D.D. Heyer, R. Loy: Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats. Brain Res 794(2), 225–38 (1998)
DOI: 10.1016/S0006-8993(98)00229-7

174. J.M. Cermak, T. Holler, D.A. Jackson, J.K. Blusztajn: Prenatal availability of choline modifies development of the hippocampal cholinergic system. FASEB J 12(3), 349–57 (1998)

175. J.M. Cermak, J.K. Blusztajn, W.H. Meck, C.L. Williams, C.M. Fitzgerald, D.L. Rosene, et al: Prenatal availability of choline alters the development of acetylcholinesterase in the rat hippocampus. Dev Neurosci 21(2), 94–104 (1999)
DOI: 10.1159/000017371

176. Q. Li, S. Guo-Ross, D.V. Lewis, D. Turner, A.M. White, W.A. Wilson, et al: Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol 91(4), 1545–55 (2004)
DOI: 10.1152/jn.00785.2003

177. D. Montoya, H.S. Swartzwelder: Prenatal choline supplementation alters hippocampal N-methyl-D-aspartate receptor-mediated neurotransmission in adult rats. Neurosci Lett 296(2-3), 85–8 (2000)
DOI: 10.1016/S0304-3940(00)01660-8

178. N.J. Sandstrom, R. Loy, C.L. Williams: Prenatal choline supplementation increases NGF levels in the hippocampus and frontal cortex of young and adult rats. Brain Res 947(1), 9–16 (2002)
DOI: 10.1016/S0006-8993(02)02900-1

179. H. Tomizawa, D. Matsuzawa, D. Ishii, S. Matsuda, K. Kawai, Y. Mashimo, et al: Methyl-donor deficiency in adolescence affects memory and epigenetic status in the mouse hippocampus. Genes Brain Behav 14(3), 301–9 (2015)
DOI: 10.1111/gbb.12207

180. L.K. Park, S. Friso, S.W. Choi: Nutritional influences on epigenetics and age-related disease. Proc Nutr Soc 71(1), 75–83 (2012)
DOI: 10.1017/S0029665111003302

181. M.J. Dauncey: Recent advances in nutrition, genes and brain health. Proc Nutr Soc 71(4), 581–91 (2012)
DOI: 10.1017/S0029665112000237

182. Z. Sezgin, Y. Dincer: Alzheimer’s disease and epigenetic diet. Neurochem Int 78,105–16 (2014)
DOI: 10.1016/j.neuint.2014.09.012

183. R.T. Bartus, R.L. Dean, J.A. Goas, A.S. Lippa: Age-related changes in passive avoidance retention: modulation with dietary choline. Science 209(4453), 301–3 (1980)
DOI: 10.1126/science.7384805

184. C.F. Lippa: Familial Alzheimer’s disease: genetic influences on the disease process. Int J Mol Med 4(5):529–36 (1999)
DOI: 10.3892/ijmm.4.5.529

185. R. Holliday: Is there an epigenetic component in long-term memory? J Theor Biol 200(3), 339–41 (1999)
DOI: 10.1006/jtbi.1999.0995

186. R.L. West, J.M. Lee, L.E. Maroun: Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J Mol Neurosci 6(2), 141–6 (1995)
DOI: 10.1007/BF02736773

187. O. Ogawa, X. Zhu, H.G. Lee, A. Raina, M.E. Obrenovich, R. Bowser, et al: Ectopic localization of phosphorylated histone H3 in Alzheimer’s disease: a mitotic catastrophe? Acta Neuropathol (Berl) 105(5), 524–8 (2003)

188. J. Gräff, D. Rei, J.S. Guan, W.Y. Wang, J. Seo, K.M. Hennig, et al: An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 483(7388), 222–6 (2012)
DOI: 10.1038/nature10849

189. C. Julien, C. Tremblay, V. Emond, M. Lebbadi, N. Salem, D.A. Bennett, et al: Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 68(1), 48–58 (2009)
DOI: 10.1097/NEN.0b013e3181922348

190. H.R. Lieberman: Nutrition, brain function and cognitive performance. Appetite 40(3), 245–54 (2003)
DOI: 10.1016/S0195-6663(03)00010-2

191. N. Kretchmer, J.L. Beard, S. Carlson: The role of nutrition in the development of normal cognition. Am J Clin Nutr 63(6), 997S – 1001S (1996)

192. L.A. Teather, R.J. Wurtman: Dietary CDP-choline supplementation prevents memory impairment caused by impoverished environmental conditions in rats. Learn Mem Cold Spring Harb N 12(1), 39–43 (2005)
DOI: 10.1101/lm.83905

193. B.M. Cohen, P.F. Renshaw, A.L. Stoll, R.J. Wurtman, D. Yurgelun-Todd, S.M. Babb: Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. JAMA 274(11), 902–7 (1995)
DOI: 10.1001/jama.274.11.902
DOI: 10.1001/jama.1995.03530110064037

194. C. Poly, J.M. Massaro, S. Seshadri, P.A. Wolf, E. Cho, E. Krall, et al: The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr 94(6), 1584–91 (2011)
DOI: 10.3945/ajcn.110.008938

195. R.J. Wurtman: A nutrient combination that can affect synapse formation. Nutrients 6(4), 1701–10 (2014)
DOI: 10.3390/nu6041701

196. P. Scheltens, J.W.R. Twisk, R. Blesa, E. Scarpini, C.A.F. von Arnim, A. Bongers, et al: Efficacy of Souvenaid in mild Alzheimer’s disease: results from a randomized, controlled trial. J Alzheimers Dis JAD 31(1), 225–36 (2012)

197. H. de Waal, C.J. Stam, M.M. Lansbergen, R.L. Wieggers, P.J.G.H. Kamphuis, P. Scheltens, et al: The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer’s disease: a randomised controlled study. PloS One 9(1), e86558 (2014)
DOI: 10.1371/journal.pone.0086558

198. H.J. Lüth, J. Apelt, A.O. Ihunwo, T. Arendt, R. Schliebs: Degeneration of beta-amyloid-associated cholinergic structures in transgenic APP SW mice. Brain Res 977(1), 16–22 (2003)
DOI: 10.1016/S0006-8993(03)02658-1

199. G.K. Wilcock, M.M. Esiri, D.M. Bowen, C.C. Smith: Alzheimer’s disease. Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities. J Neurol Sci 57(2-3), 407–17 (1982)
DOI: 10.1016/0022-510X(82)90045-4

200. N.R. Sims, D.M. Bowen, S.J. Allen, C.C. Smith, D. Neary, D.J. Thomas, et al: Presynaptic cholinergic dysfunction in patients with dementia. J Neurochem 40(2), 503–9 (1983)
DOI: 10.1111/j.1471-4159.1983.tb11311.x

201. C.H. Lin, Y.J. Huang, C.J. Lin, H.Y. Lane, G.E. Tsai: NMDA neurotransmission dysfunction in mild cognitive impairment and Alzheimer’s disease. Curr Pharm Des 20(32), 5169–79 (2014)
DOI: 10.2174/1381612819666140110115603

202. N. Fayed, P.J. Modrego, G. Rojas-Salinas, K. Aguilar: Brain glutamate levels are decreased in Alzheimer’s disease: a magnetic resonance spectroscopy study. Am J Alzheimers Dis Other Demen 26(6), 450–6 (2011)
DOI: 10.1177/1533317511421780

203. L. Svennerholm, C.G. Gottfries: Membrane lipids, selectively diminished in Alzheimer brains, suggest synapse loss as a primary event in early-onset form (type I) and demyelination in late-onset form (type II). J Neurochem 62(3), 1039–47 (1994)
DOI: 10.1046/j.1471-4159.1994.62031039.x

204. M. Söderberg, C. Edlund, K. Kristensson, G. Dallner: Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 26(6), 421–5 (1991)
DOI: 10.1007/BF02536067

205. M. Söderberg, C. Edlund, I. Alafuzoff, K. Kristensson, G. Dallner: Lipid composition in different regions of the brain in Alzheimer’s disease/senile dementia of Alzheimer’s type. J Neurochem 59(5), 1646–53 (1992)
DOI: 10.1111/j.1471-4159.1992.tb10994.x

206. R.J. Wurtman, J.K. Blusztajn, J.C. Maire: “Autocannibalism” of choline-containing membrane phospholipids in the pathogenesis of Alzheimer’s disease-A hypothesis. Neurochem Int 7(2), 369–72 (1985)
DOI: 10.1016/0197-0186(85)90127-5

207. E.J. Mufson, S.D. Ginsberg, M.D. Ikonomovic, S.T. DeKosky: Human cholinergic basal forebrain: chemoanatomy and neurologic dysfunction. J Chem Neuroanat 26(4), 233–42 (2003)
DOI: 10.1016/S0891-0618(03)00068-1

208. M.D. Ikonomovic, W.E. Klunk, E.E. Abrahamson, J. Wuu, C.A. Mathis, S.W. Scheff, et al: Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease. Neurology 77(1), 39–47 (2011)
DOI: 10.1212/WNL.0b013e3182231419

209. J. Klein, T. Holler, E. Cappel, A. Köppen, K. Löffelholz: Release of choline from rat brain under hypoxia: contribution from phospholipase A2 but not from phospholipase D. Brain Res 630(1-2), 337–40 (1993)
DOI: 10.1016/0006-8993(93)90674-C

210. M. Kozuka: Changes in brain energy metabolism, neurotransmitters, and choline during and after incomplete cerebral ischemia in spontaneously hypertensive rats. Neurochem Res 20(1), 23–30 (1995)
DOI: 10.1007/BF00995148

211. O.U. Scremin, D.J. Jenden: Focal ischemia enhances choline output and decreases acetylcholine output from rat cerebral cortex. Stroke J Cereb Circ 20(1), 92–5 (1989)
DOI: 10.1161/01.STR.20.1.92

212. R.S. Jope, X. Gu: Seizures increase acetylcholine and choline concentrations in rat brain regions. Neurochem Res 16(11), 1219–26 (1991)
DOI: 10.1007/BF00966699

213. G.L. Holmes: Epilepsy in the developing brain: lessons from the laboratory and clinic. Epilepsia 38(1), 12–30 (1997)
DOI: 10.1111/j.1528-1157.1997.tb01074.x

214. Z. Liu, A. Gatt, S.J. Werner, M.A. Mikati, G.L. Holmes: Long-term behavioral deficits following pilocarpine seizures in immature rats. Epilepsy Res 19(3), 191–204 (1994)
DOI: 10.1016/0920-1211(94)90062-0

215. A.A. Borges, P.N. Ei-Batah, L.F. Yamashita, A.D.S. Santana, A.C. Lopes, E. Freymuller-Haapalainen , et al: Neuroprotective effect of oral choline administration after global brain ischemia in rats. Nutr Neurosci 18(6), 265-74 (2014)
DOI: 10.1179/1476830514Y.0000000125

216. S.J.E. Wong-Goodrich, T.J. Mellott, M.J. Glenn, J.K. Blusztajn, C.L. Williams: Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus. Neurobiol Dis 30(2), 255–69 (2008)
DOI: 10.1016/j.nbd.2008.01.008

217. R.A. Bekdash, N.L. Harrison: Downregulation of Gabra4 expression during alcohol withdrawal is mediated by specific microRNAs in cultured mouse cortical neurons Brain Behav 5(8), e00355 (2015)
DOI: 10.1002/brb3.355

Abbreviations: Acetylcholine: Ach, Acetylcholine esterase: AchE, Acetylcholine receptor: AchR, S-adenosylhomocysteine: SAH, S-adenosylmethionine : SAM, Alzheimer disease: AD, Amyloid precursor protein: APP, Arginine:R, Brain derived neurotrophic factor: BDNF, Choline acetyltransferase : CHAT, Choline transporter: CHT, DNA methyltransferase: DNMT, Embryonic day: E, Histone acetyltransferase: HAT, Histone deacetylase: HDAC, Histone deacetylase inhibitor: HDACi, Histone methyltransferase: HMT, Huntington disease: HD, Hypothalamic-pituitary-adrenal : HPA, Insulin-like growth factor: IGF, Lysine:K, Methyl :CH3, 5-methylcytosine: 5-mC, Methyl-binding domain: MBD, Methyl-CpG- binding protein 2: MeCP2, 5-methyltetrahydrofolate: 5MTHF, Methyltetrahydrofolate reductase: MTHFR, microRNA: miR, miRNA recognition element: MRE, Muscarinic acetylcholine receptor: mAchR, Neural progenitor cell : NPC, Nicotinic acetylcholine receptor: nAchR, N-methyl-D-aspartate: NMDA, Nucleotide: nt, Parkinson’s disease: PD, Phosphotidylcholine : PC, Phosphotidylethanolamine : PEM, Post-translational modification: PTM, Repressor element-1: RE1, RNA-induced silencing complex: RISC, Serine:S, Single nucleotide polymorphism: SNP, Tetrahydrofolate: THF, 3’-untranslated region: 3’UTR

Key Words: Choline, Environment, Epigenetics, Neurodegeneration, Nutrition, Review

Send correspondence to: Rola A. Bekdash, Department of Biological Sciences, Rutgers, The State University of New Jersey, 195 University Avenue, Newark, NJ 07102, Tel: 973 353 1267, Fax: 973 353 5518, Email: rbekdash@newark.rutgers.edu