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The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

Molecular Psychiatry volume 14, pages 992–1003 (2009)Cite this article

Abstract

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a ‘Latent Early-life Associated Regulation’ (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.

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References

  1. Hardy J . A hundred years of Alzheimer's disease research. Neuron 2006; 52: 3–13.

    Article  CAS  PubMed  Google Scholar 

  2. Maslow K . 2008 Alzheimer's disease facts and figures. Alzheimer's Dement 2008; 4: 110–133.

    Article  Google Scholar 

  3. Weintraub D, Comella CL, Horn S . Parkinson's disease—Part 3: neuropsychiatric symptoms. Am J Manag Care 2008; 14 (2 Suppl): S59–S69.

    PubMed  Google Scholar 

  4. Steyaert JG, De la Marche W . What's new in autism? Eur J Pediatr 2008; 167: 1091–1101.

    Article  PubMed  Google Scholar 

  5. Gonzalez JM, Bowden CL, Katz MM, Thompson P, Singh V, Prihoda TJ et al. Development of the Bipolar Inventory of Symptoms Scale: concurrent validity, discriminant validity and retest reliability. Int J Methods Psychiatr Res 2008; 17: 198–209.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lahiri DK, Zawia NH, Greig NH, Sambamurti K, Maloney B . Early-life events may trigger biochemical pathways for Alzheimer's disease: the ‘LEARn’ model. Biogerontology 2008; 9: 375–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH . How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the ‘LEARn’ model (Latent Early Associated Regulation) may explain the triggering of AD. Curr Alzheimer Res 2007; 4: 219–228.

    Article  CAS  PubMed  Google Scholar 

  8. Lahiri DK, Maloney B . Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype. Nat Rev Neurosci 2006; 7: doi:10.1038/nrn2022-c1.

    Article  CAS  Google Scholar 

  9. Scrable H, Cavenee W, Ghavimi F, Lovell M, Morgan K, Sapienza C . A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc Natl Acad Sci USA 1989; 86: 7480–7484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW et al. The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 2005; 25: 823–829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA et al. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 2008; 28: 3–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ . Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2: 577–580.

    Article  CAS  PubMed  Google Scholar 

  13. Gluckman PD, Hanson MA, Beedle AS . Early life events and their consequences for later disease: a life history and evolutionary perspective. Am J Hum Biol 2007; 19: 1–19.

    Article  PubMed  Google Scholar 

  14. Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR et al. Epigenetic programming by maternal behavior. Nat Neurosci 2004; 7: 847–854.

    Article  CAS  PubMed  Google Scholar 

  15. Szyf M . The dynamic epigenome and its implications in toxicology. Toxicol Sci 2007; 100: 7–23.

    Article  CAS  PubMed  Google Scholar 

  16. Dosunmu R, Wu J, Adwan L, Maloney B, Basha MR, McPherson CA et al. Lifespan profiles of Alzheimer's disease-associated genes and their products in monkeys and mice: Common gene regulatory mechanisms but different pathways to Aβ production. J Alzheimers Dis 2009 (in press).

  17. Ross OA, Farrer MJ . Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. Biochem Soc Trans 2005; 33 (Part 4): 586–590.

    Article  CAS  PubMed  Google Scholar 

  18. Wirdefeldt K, Gatz M, Schalling M, Pedersen NL . No evidence for heritability of Parkinson disease in Swedish twins. Neurology 2004; 63: 305–311.

    Article  PubMed  Google Scholar 

  19. Gatz M, Pedersen NL, Berg S, Johansson B, Johansson K, Mortimer JA et al. Heritability for Alzheimer's disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci 1997; 52: M117–M125.

    Article  CAS  PubMed  Google Scholar 

  20. Bergem AL, Engedal K, Kringlen E . The role of heredity in late-onset Alzheimer disease and vascular dementia. A twin study. Arch Gen Psychiatry 1997; 54: 264–270.

    Article  CAS  PubMed  Google Scholar 

  21. Foundation NP . A Primer on Parkinson Disease 2009. [cited 3 February 2009]; available at: http://www.parkinson.org/NETCOMMUNITY/Page.aspx?pid=226&srcid=19.

  22. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045–2047.

    Article  CAS  PubMed  Google Scholar 

  23. Wu RM, Cheng CW, Chen KH, Lu SL, Shan DE, Ho YF et al. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Neurology 2001; 56: 375–382.

    Article  CAS  PubMed  Google Scholar 

  24. Dumanchin C, Camuzat A, Campion D, Verpillat P, Hannequin D, Dubois B et al. Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet 1998; 7: 1825–1829.

    Article  CAS  PubMed  Google Scholar 

  25. Hernandez F, Perez M, Gomez de Barreda E, Goni-Oliver P, Avila J . Tau as a molecular marker of development, aging, and neurodegenerative disorders. Curr Aging Sci 2008; 1: 56–61.

    Article  CAS  PubMed  Google Scholar 

  26. Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 1991; 349: 704–706.

    Article  CAS  PubMed  Google Scholar 

  27. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921–923.

    Article  CAS  PubMed  Google Scholar 

  28. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735–741.

    Article  CAS  PubMed  Google Scholar 

  29. Poorkaj P, Kas A, D'Souza I, Zhou Y, Pham Q, Stone M et al. A genomic sequence analysis of the mouse and human microtubule-associated protein tau. Mamm Genome 2001; 12: 700–712.

    Article  CAS  PubMed  Google Scholar 

  30. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996; 2: 864–870.

    Article  CAS  PubMed  Google Scholar 

  31. Zawia NH, Lahiri DK, Cardozo-Pelaez F . Epigenetics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 2009; 46: 1241–1249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hancock DB, Martin ER, Mayhew GM, Stajich JM, Jewett R, Stacy MA et al. Pesticide exposure and risk of Parkinson's disease: a family-based case–control study. BMC Neurol 2008; 8: 6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Suh YH, Checler F . Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease. Pharmacol Rev 2002; 54: 469–525.

    Article  CAS  PubMed  Google Scholar 

  34. Forman MS, Schmidt ML, Kasturi S, Perl DP, Lee VM, Trojanowski JQ . Tau and alpha-synuclein pathology in amygdala of Parkinsonism–dementia complex patients of Guam. Am J Pathol 2002; 160: 1725–1731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hare E, Glahn DC, Dassori A, Raventos H, Nicolini H, Ontiveros A et al. Heritability of age of onset of psychosis in schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2009; e-pub ahead of print.

  36. Nicholls J . A guide to autism spectrum disorders. Practitioner 2006; 250: 4–6, 9, 12.

    PubMed  Google Scholar 

  37. Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat Med 2006; 12: 824–828.

    Article  CAS  PubMed  Google Scholar 

  38. Hallmayer J, Pintado E, Lotspeich L, Spiker D, McMahon W, Petersen PB et al. Molecular analysis and test of linkage between the FMR-1 gene and infantile autism in multiplex families. Am J Hum Genet 1994; 55: 951–959.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Boksa P, El-Khodor BF . Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: possible implications for schizophrenia and other disorders. Neurosci Biobehav Rev 2003; 27: 91–101.

    Article  CAS  PubMed  Google Scholar 

  40. Dalman C, Allebeck P, Cullberg J, Grunewald C, Koster M . Obstetric complications and the risk of schizophrenia: a longitudinal study of a national birth cohort. Arch Gen Psychiatry 1999; 56: 234–240.

    Article  CAS  PubMed  Google Scholar 

  41. Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry 2008; 165: 59–65.

    Article  PubMed  Google Scholar 

  42. Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 2008; 65: 146–152.

    Article  PubMed  Google Scholar 

  43. Tsuchiya KJ, Matsumoto K, Miyachi T, Tsujii M, Nakamura K, Takagai S et al. Paternal age at birth and high-functioning autistic-spectrum disorder in offspring. Br J Psychiatry 2008; 193: 316–321.

    Article  PubMed  Google Scholar 

  44. Kinney DK, Munir KM, Crowley DJ, Miller AM . Prenatal stress and risk for autism. Neurosci Biobehav Rev 2008; 32: 1519–1532.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Geller B, Badner JA, Tillman R, Christian SL, Bolhofner K, Cook Jr EH . Linkage disequilibrium of the brain-derived neurotrophic factor Val66Met polymorphism in children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2004; 161: 1698–1700.

    Article  PubMed  Google Scholar 

  46. Ogilvie AD, Battersby S, Bubb VJ, Fink G, Harmar AJ, Goodwim GM et al. Polymorphism in serotonin transporter gene associated with susceptibility to major depression. Lancet 1996; 347: 731–733.

    Article  CAS  PubMed  Google Scholar 

  47. Ozaki N, Goldman D, Kaye WH, Plotnicov K, Greenberg BD, Lappalainen J et al. Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype. Mol Psychiatry 2003; 8: 933–936.

    Article  CAS  PubMed  Google Scholar 

  48. Frans EM, Sandin S, Reichenberg A, Lichtenstein P, Langstrom N, Hultman CM . Advancing paternal age and bipolar disorder. Arch Gen Psychiatry 2008; 65: 1034–1040.

    Article  PubMed  Google Scholar 

  49. Kaymaz N, Krabbendam L, de Graaf R, Nolen W, Ten Have M, van Os J . Evidence that the urban environment specifically impacts on the psychotic but not the affective dimension of bipolar disorder. Soc Psychiatry Psychiatr Epidemiol 2006; 41: 679–685.

    Article  PubMed  Google Scholar 

  50. Wilcox HC, Grados M, Samuels J, Riddle MA, Bienvenu 3rd OJ, Pinto A et al. The association between parental bonding and obsessive compulsive disorder in offspring at high familial risk. J Affect Disord 2008; 111: 31–39.

    Article  PubMed  Google Scholar 

  51. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ . Childhood parental loss and adult psychopathology in women. A twin study perspective. Arch Gen Psychiatry 1992; 49: 109–116.

    Article  CAS  PubMed  Google Scholar 

  52. Ashford JW, Mortimer JA . Non-familial Alzheimer's disease is mainly due to genetic factors. J Alzheimers Dis 2002; 4: 169–177.

    Article  PubMed  Google Scholar 

  53. Bales KR, Du Y, Holtzman D, Cordell B, Paul SM . Neuroinflammation and Alzheimer's disease: critical roles for cytokine/Abeta-induced glial activation, NF-kappaB, and apolipoprotein E. Neurobiol Aging 2000; 21: 427–432.

    Article  CAS  PubMed  Google Scholar 

  54. Sambamurti K, Granholm AC, Kindy MS, Bhat NR, Greig NH, Lahiri DK et al. Cholesterol and Alzheimer's disease: clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. Curr Drug Targets 2004; 5: 517–528.

    Article  CAS  PubMed  Google Scholar 

  55. Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A et al. Head trauma as a risk factor for Alzheimer's disease: a collaborative re-analysis of case–control studies. EURODEM Risk Factors Research Group. Int J Epidemiol 1991; 20 (Suppl 2): S28–S35.

    Article  PubMed  Google Scholar 

  56. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH et al. Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci USA 2001; 98: 3440–3445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hall DB, Holmlin RE, Barton JK . Oxidative DNA damage through long-range electron transfer. Nature 1996; 382: 731–735.

    Article  CAS  PubMed  Google Scholar 

  58. Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC . Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res 2004; 32: 4100–4108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Bestor TH . The DNA methyltransferases of mammals. Hum Mol Genet 2000; 9: 2395–2402.

    Article  CAS  PubMed  Google Scholar 

  60. Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP . Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 2003; 286: 355–365.

    Article  CAS  PubMed  Google Scholar 

  61. Fowler BA, Whittaker MH, Lipsky M, Wang G, Chen XQ . Oxidative stress induced by lead, cadmium and arsenic mixtures: 30-day, 90-day, and 180-day drinking water studies in rats: an overview. Biometals 2004; 17: 567–568.

    Article  CAS  PubMed  Google Scholar 

  62. Campos AC, Molognoni F, Melo FH, Galdieri LC, Carneiro CR, D'Almeida V et al. Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia 2007; 9: 1111–1121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sparks DL, Schreurs BG . Trace amounts of copper in water induce {beta}-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci USA 2003; 100: 11193–11194.

    Article  CAS  Google Scholar 

  64. Sparks DL, Friedland R, Petanceska S, Schreurs BG, Shi J, Perry G et al. Trace copper levels in the drinking water, but not zinc or aluminum influence CNS Alzheimer-like pathology. J Nutr Health Aging 2006; 10: 247–254.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Latha KS, Anitha S, Rao KS, Viswamitra MA . Molecular understanding of aluminum-induced topological changes in (CCG)12 triplet repeats: relevance to neurological disorders. Biochim Biophys Acta 2002; 1588: 56–64.

    Article  CAS  PubMed  Google Scholar 

  66. Dobosy JR, Selker EU . Emerging connections between DNA methylation and histone acetylation. Cell Mol Life Sci 2001; 58: 721–727.

    Article  CAS  PubMed  Google Scholar 

  67. Rossiello MR, Aresta AM, Prisco M, Kanduc D . DNA hypomethylation during liver cell proliferation induced by a single dose of lead nitrate. Boll Soc Ital Biol Sper 1991; 67: 993–997.

    CAS  PubMed  Google Scholar 

  68. Bolin CM, Basha R, Cox D, Zawia NH, Maloney B, Lahiri DK et al. Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. FASEB J 2006; 20: 788–790.

    Article  CAS  PubMed  Google Scholar 

  69. Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA et al. Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation. FASEB J 2005; 19: 2083–2084.

    Article  CAS  PubMed  Google Scholar 

  70. Sparks DL, Lochhead J, Horstman D, Wagoner T, Martin T . Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain. J Alzheimers Dis 2002; 4: 523–529.

    Article  CAS  PubMed  Google Scholar 

  71. Winchester PD, Huskins J, Ying J . Agrichemicals in surface water and birth defects in the United States. Acta Paediatr 2009; 98: 664–669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wu J, Basha MR, Brock B, Maloney B, Cox D, Harry J et al. Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD. J Neurosci 2008; 28: 3–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pollwein P, Masters CL, Beyreuther K . The expression of the amyloid precursor protein (APP) is regulated by two GC-elements in the promoter. Nucleic Acids Res 1992; 20: 63–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Docagne F, Gabriel C, Lebeurrier N, Lesne S, Hommet Y, Plawinski L et al. Sp1 and Smad transcription factors co-operate to mediate TGF-beta-dependent activation of amyloid-beta precursor protein gene transcription. Biochem J 2004; 383 (Part 2): 393–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lahiri DK, Robakis NK . The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences. Brain Res Mol Brain Res 1991; 9: 253–257.

    Article  CAS  PubMed  Google Scholar 

  76. La Fauci G, Lahiri DK, Salton SR, Robakis NK . Characterization of the 5′-end region and the first two exons of the beta-protein precursor gene. Biochem Biophys Res Commun 1989; 159: 297–304.

    Article  CAS  PubMed  Google Scholar 

  77. Song W, Lahiri DK . Molecular cloning of the promoter of the gene encoding the Rhesus monkey beta-amyloid precursor protein: structural characterization and a comparative study with other species. Gene 1998; 217: 151–164.

    Article  CAS  PubMed  Google Scholar 

  78. Hoffman PW, Chernak JM . DNA binding and regulatory effects of transcription factors SP1 and USF at the rat amyloid precursor protein gene promoter. Nucleic Acids Res 1995; 23: 2229–2235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Heicklen-Klein A, Ginzburg I . Tau promoter confers neuronal specificity and binds Sp1 and AP-2. J Neurochem 2000; 75: 1408–1418.

    Article  CAS  PubMed  Google Scholar 

  80. Wang CS, Burke JR, Steffens DC, Hulette CM, Breitner JC, Plassman BL . Twin pairs discordant for neuropathologically confirmed Lewy body dementia. J Neurol Neurosurg Psychiatry 2009; 80: 562–565.

    Article  PubMed  Google Scholar 

  81. Mastroeni D, Coleman PD, Grover A, Sue L, McKee A, Rogers J . Differential DNA methylation in neurons of identical twins discordant for Alzheimer's disease. Alzheimers Demen 2009; 5: P145.

    Article  Google Scholar 

  82. Guilarte TR . Prenatal lead exposure and schizophrenia: a plausible neurobiologic connection. Environ Health Perspect 2004; 112: A724.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Opler MG, Buka SL, Groeger J, McKeague I, Wei C, Factor-Litvak P et al. Prenatal exposure to lead, delta-aminolevulinic acid, and schizophrenia: further evidence. Environ Health Perspect 2008; 116: 1586–1590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jill James S, Melnyk S, Jernigan S, Hubanks A, Rose S, Gaylor DW . Abnormal transmethylation/transsulfuration metabolism and DNA hypomethylation among parents of children with autism. J Autism Dev Disord 2008; 30: 1966–1976.

    Article  Google Scholar 

  85. Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F et al. Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 2006; 15: 3132–3145.

    Article  CAS  PubMed  Google Scholar 

  86. Abdolmaleky HM, Cheng KH, Russo A, Smith CL, Faraone SV, Wilcox M et al. Hypermethylation of the reelin (RELN) promoter in the brain of schizophrenic patients: a preliminary report. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 60–66.

    Article  Google Scholar 

  87. Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T et al. Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 459–462.

    Article  PubMed  Google Scholar 

  88. Grayson DR, Chen Y, Costa E, Dong E, Guidotti A, Kundakovic M et al. The human reelin gene: transcription factors (+), repressors (−) and the methylation switch (+/−) in schizophrenia. Pharmacol Ther 2006; 111: 272–286.

    Article  CAS  PubMed  Google Scholar 

  89. McGowan PO, Sasaki A, Huang TC, Unterberger A, Suderman M, Ernst C et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE 2008; 3: e2085.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 2008; 82: 696–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H et al. Intra-individual change over time in DNA methylation with familial clustering. JAMA 2008; 299: 2877–2883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ et al. Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 2008; 28: 6904–6913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kanvah S, Schuster GB . The sacrificial role of easily oxidizable sites in the protection of DNA from damage. Nucleic Acids Res 2005; 33: 5133–5138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Knudson Jr AG . Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68: 820–823.

    Article  PubMed  PubMed Central  Google Scholar 

  95. 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 2004; 429: 883–891.

    Article  CAS  PubMed  Google Scholar 

  96. Zhu X, Raina AK, Perry G, Smith MA . Alzheimer's disease: the two-hit hypothesis. Lancet Neurol 2004; 3: 219–226.

    Article  CAS  PubMed  Google Scholar 

  97. Whitelaw NC, Whitelaw E . How lifetimes shape epigenotype within and across generations. Hum Mol Genet 2006; 15: R131–R137.

    Article  CAS  PubMed  Google Scholar 

  98. van Vliet J, Oates NA, Whitelaw E . Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 2007; 64: 1531–1538.

    Article  CAS  PubMed  Google Scholar 

  99. De la Burde B, Choat MS . Does asymptomatic lead exposure in children have latent sequelae? J Pediatr 1972; 81: 1088–1091.

    Article  CAS  PubMed  Google Scholar 

  100. Liu Y . Like father like son. A fresh review of the inheritance of acquired characteristics. EMBO Rep 2007; 8: 798–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gorelick R . Neo-Lamarckian medicine. Med Hypotheses 2004; 62: 299–303.

    Article  CAS  PubMed  Google Scholar 

  102. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KV et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci USA 2003; 100: 2538–2543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Anway MD, Skinner MK . Epigenetic transgenerational actions of endocrine disruptors. Endocrinology 2006; 147 (6 Suppl): S43–S49.

    Article  CAS  PubMed  Google Scholar 

  104. Anway MD, Cupp AS, Uzumcu M, Skinner MK . Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005; 308: 1466–1469.

    Article  CAS  PubMed  Google Scholar 

  105. Chan A, Shea TB . Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress. J Alzheimers Dis 2006; 10: 353–358.

    Article  CAS  PubMed  Google Scholar 

  106. Lahiri DK . Where the actions of environment (nutrition), gene and protein meet: beneficial role of fruit and vegetable juices in potentially delaying the onset of Alzheimer's disease. J Alzheimer Dis 2006; 10: 359–361.

    Article  CAS  Google Scholar 

  107. Lahiri DK, XU Y, Klaunig J, Baiyewu O, Ogunniyi A et al. Effect of oxidative stress on DNA damage and beta-amyloid precursor proteins in lymphoblastoid cell lines from a nigerian population. Ann NY Acad Sci 1999; 893: 331–336.

    Article  CAS  PubMed  Google Scholar 

  108. Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH . Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 2004; 36: 224–231.

    Article  CAS  PubMed  Google Scholar 

  109. Buehlmeyer K, Doering F, Daniel H, Kindermann B, Schulz T, Michna H . Alteration of gene expression in rat colon mucosa after exercise. Ann Anat 2008; 190: 71–80.

    Article  CAS  PubMed  Google Scholar 

  110. Kivipelto M, Solomon A . Alzheimer's disease—the ways of prevention. J Nutr Health Aging 2008; 12: 89S–94S.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the Alzheimer's association and NIH (AG18379 and AG18884) to DKL. We acknowledge the critique and suggestions made by JI Nurnberger for this paper.

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  1. Department of Psychiatry, Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    D K Lahiri & B Maloney

  2. Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    D K Lahiri

  3. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA

    N H Zawia

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  1. D K Lahiri
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  2. B Maloney
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  3. N H Zawia
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Correspondence to D K Lahiri.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Lahiri, D., Maloney, B. & Zawia, N. The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 14, 992–1003 (2009). https://doi.org/10.1038/mp.2009.82

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  • DOI: https://doi.org/10.1038/mp.2009.82

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