Abstract
The prominent symptoms of Alzheimer’s disease (AD) include severe loss of memory, failure of cognition and reasoning, and overall deficit of other intellectual abilities. AD usually appears late in adult life, but when the disease initiates and how long the disease processes take to develop are presently unknown. To address this issue, the “Latent Early–life Associated Regulation” (LEARn) model has been proposed. This model explains the etiology of AD and integrates both the neuropathological features (e.g., amyloid-beta plaques and hyperphosphorylated tau tangles) and environmental conditions (e.g., dietary imbalance, metal exposure, and pestichemicals) associated with AD. As per the LEARn model, environmental agents could perturb gene regulation in a long–term fashion, beginning at early developmental stages, but these perturbations would not have pathological results until significantly later in life, if an additional perturbation were to occur. The LEARn model postulates latent expression of specific genes triggered at an early stage of life. The LEARn model operates via the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. Thus, the LEARn model unifies genetic and environmental risk factors to explain the etiology of the most common, sporadic form of AD. Finally, the possible medical remediation is discussed with reference to the relatively long term of latency under the LEARn model.
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Barker DJ, Eriksson JG, Forsen T, Osmond C (2002) Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 31(6):1235–1239
Basha MR, Wei W, Bakheet SA, Benitez N, Siddiqi HK, Ge YW, Lahiri DK, Zawia NH (2005) The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25(4):823–829
Bellingham SA, Lahiri DK, Maloney B, La Fontaine S, Multhaup G, Camakaris J (2004) Copper depletion down-regulates expression of the Alzheimer’s disease amyloid-beta precursor protein gene. J Biol Chem 279(19):20378–20386
Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekstrom TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299(24):2877–2883
Bolin CM, Basha R, Cox D, Zawia NH, Maloney B, Lahiri DK, Cardozo-Pelaez F (2006) Exposure to lead and the developmental origin of oxidative DNA damage in the aging brain. FASEB J 20(6):788–790
Buehlmeyer K, Doering F, Daniel H, Kindermann B, Schulz T, Michna H (2008) Alteration of gene expression in rat colon mucosa after exercise. Ann Anat 190(1):71–80
Campos AC, Molognoni F, Melo FH, Galdieri LC, Carneiro CR, D’Almeida V, Correa M, Jasiulionis MG (2007) Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia 9(12):1111–1121
Chan A and Shea TB (2006) Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress. J Alzheimers Dis 10(4):353–358
De la Burde B and Choat MS (1972) Does asymptomatic lead exposure in children have latent sequelae? J Pediatrics 81(6):1088–1091
Dobosy JR and Selker EU (2001) Emerging connections between DNA methylation and histone acetylation. Cell Mol Life Sci 58:721–727
Fowler BA, Whittaker MH, Lipsky M, Wang G, Chen XQ (2004) Oxidative stress induced by lead, cadmium and arsenic mixtures: 30-day, 90-day, and 180-day drinking water studies in rats: an overview. Biometals 17(5–6):567–568
Galic MA, Riazi K, Heida JG, Mouihate A, Fournier NM, Spencer SJ, Kalynchuk LE, Teskey GC, Pittman QJ (2008) Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 28:6904–6913
Ge Y-W, Maloney B, Alley GM, Lahiri DK (2007) Important differences between human and mouse APOE gene promoters: implications in Alzheimer’s Disease. J Neurochem 103(3):1237–1257
Gmitterova K, Heinemann U, Gawinecka J, Varges D, Ciesielczyk B, Valkovic P, Benetin J, Zerr I (2009) 8-OHdG in cerebrospinal fluid as a marker of oxidative stress in various neurodegenerative diseases. Neurodegener Dis 6(5–6):263–269
Hall K, Murrell J, Ogunniyi A, Deeg M, Baiyewu O, Gao S, Gureje O, Dickens J, Evans R, Smith-Gamble V, Unverzagt FW, Shen J, Hendrie H (2006) Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology 66(2):223–227
Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A (2001) Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 98(18):10469–10474
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (2003) Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol 60(8):1119–1122
Herms J, Anliker B, Heber S, Ring S, Fuhrmann M, Kretzschmar H, Sisodia S, Muller U (2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J 23(20):4106–4115
Hughes LA, Van Den Brandt PA, de Bruine AP, Wouters KA, Hulsmans S, Spiertz A, Goldbohm RA, de Goeij AF, Herman JG, Weijenberg MP, van Engeland M (2009) Early life exposure to famine and colorectal cancer risk: a role for epigenetic mechanisms. PLoS One 4(11):e7951
Kikuchi Y, Yasuhara T, Agari T, Kondo A, Kuramoto S, Kameda M, Kadota T, Baba T, Tajiri N, Wang F, Tayra JT, Hanbai L, Miyoshi Y, Borlongan CV, Date I (2010) Urinary 8-OHdG elevations in a partial lesion rat model of Parkinson’s disease correlate with behavioral symptoms and nigrostriatal dopaminergic depletion. J Cell Physiol. doi:10.1002/jcp.22467
Kivipelto M and Solomon A (2008) Alzheimer’s disease—the ways of prevention. J Nutr Health Aging 12(1):89S–94S
Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 68(4):820–823
Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH (2004) Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. J Pineal Res 36(4):224–231
Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider LS (2003) A critical analysis of new molecular targets and strategies for drug developments in Alzheimer’s disease. Curr Drug Targets 4(2):97–112
Lahiri DK and Maloney B (2006) Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype. Nat Rev Neurosci 7. doi:10.1038/nrn2022-c1
Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH (2007) 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 4(2):219–228
Lahiri DK, Maloney B, Zawia NH (2009) The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases. Mol Psychiatry 14(11):992–1003. doi:mp200982 [pii] 10.1038/mp.2009.82
Lahiri DK, Wavrant De-Vrieze F, Ge Y-W, Maloney B, Hardy J (2005) Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer’s disease. Neurobiol Aging 26(10):1329–1341
Levenson VV (2010) DNA methylation as a universal biomarker. Expert Rev Mol Diagn 10(4):481–488
Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429(6994):883–891
Mastroeni D, Coleman PD, Grover A, Sue L, McKee A, Rogers J (2009a) Differential DNA methylation in neurons of identical twins discordant for Alzheimer’s disease. Alzheimers Dement 5:p 145
Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD (2009b) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One 4(8):e6617
Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmuhl Y, Fischer D, Holsboer F, Wotjak CT, Almeida OF, Spengler D (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12(12):1559–1566
Nakajima T, Enomoto S, Yamashita S, Ando T, Nakanishi Y, Nakazawa K, Oda I, Gotoda T, Ushijima T (2010) Persistence of a component of DNA methylation in gastric mucosae after Helicobacter pylori eradication. J Gastroenterol 45(1):37–44
Paschos K, Smith P, Anderton E, Middeldorp JM, White RE, Allday MJ (2009) Epstein-barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim. PLoS Pathog 5(6):e1000492
Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, Willis RJ, Wallace RB (2007) Prevalence of dementia in the United States: the aging, demographics, and memory study. Neuroepidemiology 29(1–2):125–132
Sambamurti K, Suram A, Venugopal C, Prakasam A, Zhou Y, Lahiri DK, Greig NH (2006) A partial failure of membrane protein turnover may cause Alzheimer’s disease: a new hypothesis. Curr Alzheimer Res 3(1):81–90
Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP (2003) Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286(2):355–365
Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC (2004) Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucl Acids Res 32(14):4100–4108
Van Vliet J, Oates NA, Whitelaw E (2007) Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 64(12):1531–1538
Whitelaw NC, Whitelaw E (2006) How lifetimes shape epigenotype within and across generations. Hum Mol Genet 15(1):R131–137
Wu J, Basha MR, Brock B, Cox DP, Cardozo-Pelaez F, McPherson CA, Harry J, Rice DC, Maloney B, Chen D, Lahiri DK, Zawia NH (2008) 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 28(1):3–9
Zeh JA, Zeh DW (2008) Maternal inheritance, epigenetics and the evolution of polyandry. Genetica 134:45–54
Zhang S, Barros SP, Niculescu MD, Moretti AJ, Preisser JS, Offenbacher S (2010) Alteration of PTGS2 promoter methylation in chronic periodontitis. J Dent Res 89(2):133–137
Alzheimer’s Association (2012) Alzheimer’s disease facts and figures. Alzheimer’s & Dementia 8(2):14–15
Notice of Violation (2010) Notice of violation of the safe drinking water and toxic enforcement act of 1986 (proposition 65), section 25249.6 of the California health and safety code, for exposing consumers of apple juice, grape juice, packaged peaches, packaged pears, and fruit cocktail to lead. http://www.envirolaw.org/documents/100609-NoticeLetterwithExhibits.PDF. Accessed 11 June 2010
Acknowledgements
This work was supported by grants from the Alzheimer’s association 11-206418, and NIH (AG18379 and AG18884) to DKL, and Indiana Alzheimer’s Disease Center grant (IADC) to Dr. B. Ghetti.
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Lahiri, D.K. (2012). Brain Aging: Influence of Early–Life Events on Late-Life Brain Disorders. In: Thakur, M., Rattan, S. (eds) Brain Aging and Therapeutic Interventions. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5237-5_5
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