The "lEARn" (latent early-life associated regulation) model: An epigenetic pathway linking metabolic and cognitive disorders

Journal of Alzheimer's Disease

Volumn 30, Issue SUPPL.2, 2012, Pages

  Lahiri, Debomoy K ^a   Maloney, Bryan ^a  

^a INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Epigenetic; epigenomic; gene regulation; idiopathic disease; metabolic cognitive syndrome; sporadic disease; two hit

Indexed keywords

AMYLOID PRECURSOR PROTEIN; BETA SECRETASE 1; DNA METHYLTRANSFERASE; MESSENGER RNA; METHYL CPG BINDING PROTEIN 2; TRANSCRIPTION FACTOR SP1;

ACE GENE; ADORA1 GENE; ALZHEIMER DISEASE; CARDIOVASCULAR DISEASE; COGNITIVE DEFECT; CPG ISLAND; DIABETES MELLITUS; DISEASE ASSOCIATION; DNA METHYLATION; ECE1 GENE; ENVIRONMENTAL FACTOR; EPIGENETICS; GENE; GENE SEQUENCE; HUMAN; HYPERTENSION; IDE GENE; METABOLIC COGNITIVE SYNDROME; METABOLIC SYNDROME X; MODEL; NUTRITION; OXIDATION; PPARG GENE; PRIORITY JOURNAL; PRKACA GENE; REVIEW; SORCS1 GENE;

EID: 84863007261     PISSN: 13872877     EISSN: 18758908     Source Type: Journal    
DOI: 10.3233/JAD-2012-120373     Document Type: Review

References (153)

1. Thies W, Bleiler L (2011) 2011 Alzheimer's disease facts and figures. Alzheimers Dement 7, 208-244.
2. Lahiri DK, Farlow MR, Greig NH, Sambamurti K (2002) Current drug targets for Alzheimer's disease treatment. Drug Devel Res 56, 267-281. (Pubitemid 35168304)
3. Iqbal K, Liu F, Gong CX, Grundke-Iqbal I (2010) Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 7, 656-664.
4. Delacourte A (2008) Tau pathology and neurodegeneration: An obvious but misunderstood link. J Alzheimers Dis 14, 437-440.
5. Delacourte A (2005) Tauopathies: Recent insights into old diseases. Folia Neuropathol 43, 244-257. (Pubitemid 43109283)
6. Tanzi RE, Bertram L (2005) Twenty yearsofthe Alzheimer's disease amyloid hypothesis: A genetic perspective. Cell 120, 545-555. (Pubitemid 40269768)
7. Snider BJ, Fagan AM, Roe C, Shah AR, Grant EA, Xiong C, Morris JC, Holtzman DM (2009) Cerebrospinal fluid biomarkers and rate ofcognitive declineinvery mild dementia of the Alzheimer type. Arch Neurol 66, 638-645.
8. Lv H, Jia L, Jia J (2008) Promoter polymorphisms which modulate APP expression may increase susceptibility to Alzheimer's disease. Neurobiol Aging 29, 194-202.
9. Walsh DM, Klyubin I, Shankar GM, Townsend M, Fadeeva JV, Betts V, Podlisny MB, Cleary JP, Ashe KH, Rowan MJ, Selkoe DJ (2005) The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention. Biochem Soc Trans 33, 1087-1090. (Pubitemid 41659119)
10. Ohyagi Y (2008) Intracellular amyloid beta-protein as a therapeutic target for treating Alzheimer's disease. Curr Alzheimer Res 5, 555-561.
11. Hardy J (2009) The amyloid hypothesis for Alzheimer's disease: A critical reappraisal. J Neurochem 110, 1129-1134.
12. Fujigasaki H, Naruse S, Kaneko K, Hirasawa H, Tsuji S, Miyatake T (1994) Mutational analysis of the amyloid precursor protein gene inJapanese familial Alzheimer's disease kindreds. Hum Genet 93, 460-462. (Pubitemid 24106476)
13. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 360, 672-674. (Pubitemid 23007680)
14. Xia W, Ostaszewski BL, Kimberly WT, Rahmati T, Moore CL, Wolfe MS, Selkoe DJ (2000) FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: Evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. Neurobiol Dis 7, 673-681. (Pubitemid 32044291)
15. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) 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 2, 864-870. (Pubitemid 26296755)
16. Small DH, Klaver DW, Foa L (2010) Presenilins and the gamma-secretase: Still a complex problem. Mol Brain 3, 7.
17. Lahiri DK, Maloney B (2010) Beyond the signaling effect role of amyloid-beta (42) on the processing of APP, and its clinical implications. Exp Neurol 225, 51-54.
18. Bailey JA, Maloney B, Ge YW, Lahiri DK (2011) Functional activityofthe novelAlzheimer'samyloid beta-peptide interacting domain (AbetaID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis. Gene 488, 13-22.
19. Maloney B, Lahiri DK (2011) The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: Characterizing a new regulatory motif. Gene 488, 1-12.
20. Igbavboa U, Sun GY, Weisman GA, He Y, Wood WG (2009) Amyloid beta-protein stimulates trafficking of cholesterol and caveolin-1 from the plasma membrane to the Golgi complex in mouse primary astrocytes. Neuroscience 162, 328-338.
21. Huang Y (2006) Apolipoprotein E and Alzheimer disease. Neurology 66, S79-S85. (Pubitemid 43739990)
22. Lahiri DK, Sambamurti K, Bennett DA (2004) Apolipopro-tein gene and its interaction with the environmentally driven risk factors: Molecular, genetic and epidemiological studies of Alzheimer's disease. Neurobiol Aging 25, 651-660. (Pubitemid 38686488)
23. Hu J, Igarashi A, Kamata M, Nakagawa H (2001) Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta) ; retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 276, 47863-47868.
24. Funalot B, Ouimet T, Claperon A, Fallet C, Delacourte A, Epelbaum J, Subkowski T, Leonard N, Codron V, David JP, Amouyel P, Schwartz JC, Helbecque N (2004) Endothelin-converting enzyme-1 is expressed in human cerebral cortex and protects against Alzheimer's disease. Mol Psychiatry 9, 1122-1128, 1059. (Pubitemid 40065457)
25. Zuo X, Jia J (2009) Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease. Brain Res 1249, 1-8.
26. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, Nalls MA, Chen K, Lee W, Chewning K, Villa SE, Meechoovet HB, Gerber JD, Frost D, Benson HL, O'Reilly S, Chibnik LB, Shulman JM, Singleton AB, Craig DW, Van Keuren-Jensen KR, Dunckley T, Bennett DA, De Jager PL, Heward C, Hardy J, Reiman EM, Huentelman MJ (2010) Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neu-ropathologically verified individuals. Hum Mol Genet 19, 3295-3301.
27. Lambert JC, Zelenika D, Hiltunen M, Chouraki V, Com-barros O, Bullido MJ, Tognoni G, Fievet N, Boland A, Arosio B, Coto E, Del Zompo M, Mateo I, Frank-Garcia A, Helisalmi S, Porcellini E, Pilotto A, Forti P, Ferri R, Delepine M, Scarpini E, Siciliano G, Solfrizzi V, Sorbi S, Spalletta G, Ravaglia G, Valdivieso F, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossu P, Piccardi P, Annoni G, Seripa D, Galimberti D, Licastro F, Lath-rop M, Soininen H, Amouyel P (2011) Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations. Neurobiol Aging 32, 756, e711-e755.
28. Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, Jimenez-Velazquez IZ, Rogaeva E, St George-Hyslop PH, Mayeux R (2011) Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol 68, 320-328.
29. Bertram L, McQueen M, Mullin K, Blacker D, Tanzi R, The AlzGene Database, http://www.alzgene.org/, Accessed 1 December 2011.
30. Markesbery WR (2010) Neuropathologic alterations in mild cognitive impairment: A review. J Alzheimers Dis 19, 221-228.
31. Sabbagh MN, Cooper K, DeLange J, Stoehr JD, Thind K, Lahti T, Reisberg B, Sue L, Vedders L, Fleming SR, Beach TG (2010) Functional, global and cognitive decline correlates to accumulation of Alzheimer's pathology in MCI and AD. Curr Alzheimer Res 7, 280-286.
32. Berg L, McKeel DW Jr, Miller JP, Storandt M, Rubin EH, Morris JC, Baty J, Coats M, Norton J, Goate AM, Price JL, Gearing M, Mirra SS, Saunders AM (1998) Clinicopatho-logic studies in cognitively healthy aging and Alzheimer's disease: Relation of histologic markers to dementia severity, age, sex, and apolipoprotein E genotype. Arch Neurol 55, 326-335. (Pubitemid 28146197)
33. Ogunniyi A, Baiyewu O, Gureje O, Hall KS, Unverzagt F, Siu SH, Gao S, Farlow M, Oluwole OS, Komolafe O, Hendrie HC (2000) Epidemiology of dementia in Nigeria: Results from the Indianapolis-Ibadan study. Eur J Neurol 7, 485-490. (Pubitemid 32530107)
34. Scarmeas N, Stern Y (2003) Cognitive reserve and lifestyle. J Clin Exp Neuropsychol 25, 625-633. (Pubitemid 36808148)
35. Miller DB, O'Callaghan JP (2008) Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases? Metabolism 57 (Suppl 2) , S44-S49.
36. Bolin CM, Basha R, Cox D, Zawia NH, Maloney B, Lahiri DK, Cardozo-Pelaez F (2006) Exposure to lead and the developmental originof oxidative DNA damagein the aging brain. FASEB J 20, 788-790. (Pubitemid 46671216)
37. 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, 20378-20386. (Pubitemid 38623484)
38. Rogers JT, Lahiri DK (2004) Metal and inflammatory targets for Alzheimer's disease. Curr Drug Targets 5, 535-551. (Pubitemid 39004428)
39. Sambamurti K, Granholm AC, Kindy MS, Bhat NR, Greig NH, Lahiri DK, Mintzer JE (2004) Cholesterol and Alzheimer's disease: Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. Curr Drug Targets 5, 517-528. (Pubitemid 39004426)
40. Sparks DL, Lochhead J, Horstman D, Wagoner T, Martin T (2002) Water quality has apronounced effect oncholesterol-induced accumulation ofAlzheimer amyloid beta (Abeta) in rabbit brain. J Alzheimers Dis 4, 523-529. (Pubitemid 36142842)
41. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, Petot GJ, Debanne SM (2001) Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A 98, 3440-3445. (Pubitemid 32220864)
42. Mortimer JA, van Duijn CM, Chandra V, Fratiglioni L, Graves AB, Heyman A, Jorm AF, Kokmen E, Kondo K, Rocca WA et al. (1991) 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 20 (Suppl 2) , S28-S35.
43. Bales KR, Du Y, Holtzman D, Cordell B, Paul SM (2000) Neuroinflammation and Alzheimer's disease: Critical roles for cytokine/Abeta-induced glial activation, NF-kappa B, and apolipoprotein E. Neurobiol Aging 21, 427-432. (Pubitemid 30349109)
44. Friedland RP, Fritsch T, Smyth KA, Koss E, Lerner AJ, Chen CH, Petot GJ, Debanne SM (2001) Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A 98, 3440-3445. (Pubitemid 32220864)
45. 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, 223-227. (Pubitemid 43970158)
46. Evans RM, Hui S, Perkins A, Lahiri DK, Poirier J, Far-low MR (2004) Cholesterol and APOE genotype interact to influence Alzheimer disease progression. Neurology 62, 1869-1871. (Pubitemid 38661755)
47. Lahiri DK (2004) Apolipoproteineasatarget for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene. J Mol Neurosci 23, 225-234.
48. Gureje O, Ogunniyi A, Baiyewu O, Price B, Unverzagt FW, Evans RM, Smith-Gamble V, Lane KA, Gao S, Hall KS, Hendrie HC, Murrell JR (2006) APOE epsilon4 is not associated with Alzheimer's disease in elderly Nigerians. Ann Neurol 59, 182-185. (Pubitemid 43042886)
49. Wachsman JT (1997) DNA methylation and the association between genetic and epigenetic changes: Relation to carcinogenesis. Mutat Res 375, 1-8. (Pubitemid 27152196)
50. Song CX, Szulwach KE, Fu Y, Dai Q, Yi C, Li X, Li Y, Chen CH, Zhang W, Jian X, Wang J, Zhang L, Looney TJ, Zhang B, Godley LA, Hicks LM, Lahn BT, Jin P, He C (2011) Selective chemical labeling reveals the genome-wide distribution of 5-hydroxymethylcytosine. Nat Biotechnol 29, 68-72.
51. Ghosh R, Mitchell DL (1999) Effect ofoxidative DNA damage in promoter elements on transcription factor binding. Nucleic Acids Res 27, 3213-3218. (Pubitemid 29355738)
52. Kuo MH, vom Baur E, Struhl K, Allis CD (2000) Gcn4 activator targets Gcn5 histone acetyltransferase to specific promoters independently of transcription. Mol Cell 6, 1309-1320. (Pubitemid 32045924)
53. Sims RJ 3rd, Nishioka K, Reinberg D (2003) Histone lysine methylation: A signature for chromatin function. Trends Genet 19, 629-639. (Pubitemid 37338383)
54. van Vliet J, Oates NA, Whitelaw E (2007) Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 64, 1531-1538. (Pubitemid 46954151)
55. Zelko IN, Mueller MR, Folz RJ (2010) CpG methy-lation attenuates Sp1 and Sp3 binding to the human extracellular superoxide dismutase promoter and regulates its cell-specific expression. Free Radic Biol Med 48, 895-904.
56. Wu J, Basha MR, Zawia NH (2008) The environment, epi-genetics and amyloidogenesis. J Mol Neurosci 34, 1-7.
57. Feng Q, Zhang Y (2001) The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes Dev 15, 827-832. (Pubitemid 32295063)
58. Mulero-Navarro S, Esteller M (2008) Epigenetic biomarkers for human cancer: The time is now. Crit Rev Oncol Hematol 68, 1-11.
59. Fuso A, Seminara L, Cavallaro RA, D'Anselmi F, Scarpa S (2005) S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production. Mol Cell Neurosci 28, 195-204. (Pubitemid 39656023)
60. Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J (2010) Epigenetic changes in Alzheimer's disease: Decrements in DNA methylation. Neurobiol Aging31, 2025-2037.
61. Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD (2009) Epigenetic differencesin cortical neurons from apair of monozygotic twins discordant for Alzheimer's disease. PLoS One 4, e6617.
62. 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, 2877-2883. (Pubitemid 351930887)
63. Wang SC, Oelze B, Schumacher A (2008) Age-specific epi-genetic drift in late-onset Alzheimer's disease. PLoS One 3, e2698.
64. Zawia NH, Lahiri DK, Cardozo-Pelaez F (2009) Epigenet-ics, oxidative stress, and Alzheimer disease. Free Radic Biol Med 46, 1241-1249.
65. Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neu-rosci 7, 847-854. (Pubitemid 38989508)
66. 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, e7951.
67. Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP (2003) Effects of cadmium on DNA- (Cytosine-5) methyl-transferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286, 355-365. (Pubitemid 36566447)
68. Kim KY, Kim DS, Lee SK, Lee IK, Kang JH, Chang YS, Jacobs DR, Steffes M, Lee DH (2010) Association of low-dose exposure to persistent organic pollutants with global DNA hypomethylation in healthy Koreans. Environ Health Perspect 118, 370-374.
69. Desaulniers D, Xiao GH, Lian H, Feng YL, Zhu J, Nakai J, Bowers WJ (2009) Effects of mixtures of polychlorinated biphenyls, methylmercury, and organochlorine pesticides on hepatic DNA methylation in prepubertal female Sprague-Dawley rats. Int J Toxicol 28, 294-307.
70. Guo JU, Su Y, Zhong C, Ming GL, Song H (2011) Hydrox-ylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423-434.
71. Muenzel M, Globisch D, Bruekl T, Wagner M, Welzmiller V, Stylianos M, Mueller M, Biel M, Carell T (2010) Quantification of the sixth DNA base hydroxymethylcytosine in the brain. Angew Chem Int Ed Engl 49, 5375-5377.
72. Kriaucionis S, Heintz N (2009) The nuclear DNA base 5- hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324, 929-930.
73. Lee YA, Durandin A, Dedon PC, Geacintov NE, Shafirovich V (2008) Oxidation of guanine in G, GG, and GGG sequence contexts by aromatic pyrenyl radical cations and carbonate radical anions: Relationship between kinetics and distribution of alkali-labile lesions. J Phys Chem B 112, 1834-1844. (Pubitemid 351316388)
74. Ammendola R, Mesuraca M, Russo T, Cimino F (1994) The DNA-binding efficiencyofSp1isaffectedbyredox changes. Eur J Biochem 225, 483-489.
75. Dosunmu R, Wu J, Adwan L, Maloney B, Basha MR, McPherson CA, Harry GJ, Rice DC, Zawia NH, Lahiri DK (2009) Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice. J Alzheimers Dis 18, 211-230.
76. Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W (2005) Distinct transcriptional regulation and functionofthe human BACE2 and BACE1 genes. FASEB J 19, 739-749. (Pubitemid 40617378)
77. 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). Nucleic Acids Res 32, 4100-4108. (Pubitemid 39232282)
78. Weitzman SA, Turk PW, Milkowski DH, Kozlowski K (1994) Free radical adducts induce alterations in DNA cyto-sine methylation. Proc Natl Acad Sci U S A 91, 1261-1264. (Pubitemid 24058990)
79. Saquib Q, Al-Khedhairy AA, Singh BR, Arif JM, Musar-rat J (2010) Genotoxic fungicide methyl thiophanate as an oxidative stressor inducing 8-oxo-7, 8-dihydro-2' -deoxyguanosine adducts in DNA and mutagenesis. J Environ Sci Health B 45, 40-45.
80. Bagchi D, Bagchi M, Hassoun EA, Stohs SJ (1995) In vitro and in vivo generation of reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides. Toxicology 104, 129-140. (Pubitemid 26016384)
81. Weill FS, Cela EM, Ferrari A, Paz ML, Leoni J, Gonzalez Maglio DH (2011) Skin exposure to chronic but not acute UV radiation affects peripheral T-cell function. J Toxicol Environ Health A 74, 838-847.
82. Risom L, Moller P, Loft S (2005) Oxidative stress-induced DNA damage by particulate air pollution. Mutat Res 592, 119-137. (Pubitemid 41714049)
83. Djuric Z, Lewis SM, Lu MH, Mayhugh M, Tang N, Hart RW (2001) Effect of varying dietary fat levels on rat growth and oxidative DNA damage. Nutr Cancer 39, 214-219. (Pubitemid 33694038)
84. Croteau DL, de Souza-Pinto NC, Harboe C, Keijzers G, Zhang Y, Becker K, Sheng S, Bohr VA (2010) DNA repair and the accumulation of oxidatively damaged DNA are affected by fruit intake in mice. J Gerontol A Biol Sci Med Sci 65, 1300-1311.
85. Thompson HJ, Heimendinger J, Diker A, O'Neill C, Haegele A, Meinecke B, Wolfe P, Sedlacek S, Zhu Z, Jiang W (2006) Dietary botanical diversity affects the reduction of oxidative biomarkers in women due to high vegetable and fruit intake. J Nutr 136, 2207-2212. (Pubitemid 44156826)
86. Cui L, Hofer T, Rani A, Leeuwenburgh C, Foster TC (2009) Comparison of lifelong and late life exercise on oxidative stress in the cerebellum. Neurobiol Aging 30, 903-909.
87. Bloomer RJ, Fisher-Wellman KH (2008) Blood oxidative stress biomarkers: Influence of sex, exercise training status, and dietary intake. Gend Med 5, 218-228.
88. Pinlaor S, Ma N, Hiraku Y, Yongvanit P, Semba R, Oikawa S, Murata M, Sripa B, Sithithaworn P, Kawanishi S (2004) Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7, 8-dihydro-2'-deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis 25, 1535-1542. (Pubitemid 39162719)
89. Narushima S, Spitz DR, Oberley LW, Toyokuni S, Miyata T, Gunnett CA, Buettner GR, Zhang J, Ismail H, Lynch RG, Berg DJ (2003) Evidence for oxidative stress in NSAID-induced colitis in IL10minus/minus mice. Free Radic Biol Med34, 1153-1166. (Pubitemid 36423366)
90. Shen Z, Wu W, Hazen SL (2000) Activated leukocytes oxidatively damage DNA, RNA, and the nucleotide pool through halide-dependent formation of hydroxyl radical. Biochemistry 39, 5474-5482. (Pubitemid 30257089)
91. Cecchi C, Fiorillo C, Sorbi S, Latorraca S, Nacmias B, Bagnoli S, Nassi P, Liguri G (2002) Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer's patients. Free Radic Biol Med 33, 1372-1379. (Pubitemid 35284921)
92. Butterfield DA (2002) Amyloid beta-peptide (1-42) -induced oxidative stress and neurotoxicity: Implications for neu-rodegeneration in Alzheimer's disease brain. A review. Free Radic Res 36, 1307-1313. (Pubitemid 35469517)
93. Paschos K, Allday MJ (2010) Epigenetic reprogramming of host genes in viral and microbial pathogenesis. Trends Microbiol 18, 439-447.
94. Feng Q, Zhang Y (2003) The NuRD complex: Linking histone modification to nucleosome remodeling. Curr Top Microbiol Immunol 274, 269-290. (Pubitemid 36118995)
95. Sarkar S, Abujamra AL, Loew JE, Forman LW, Perrine SP, Faller DV (2011) Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling. Anticancer Res 31, 2723-2732.
96. Chodavarapu RK, Feng S, Bernatavichute YV, Chen PY, Stroud H, Yu Y, Hetzel JA, Kuo F, Kim J, Cokus SJ, Casero D, Bernal M, Huijser P, Clark AT, Kramer U, Merchant SS, Zhang X, Jacobsen SE, Pellegrini M (2010) Relationship between nucleosome positioning and DNA methylation. Nature 466, 388-392.
97. Kim HS, Kim EM, Kim NJ, Chang KA, Choi Y, Ahn KW, Lee JH, Kim S, Park CH, Suh YH (2004) Inhibition of histone deacetylation enhances the neurotoxicity induced by the C-terminal fragments of amyloid precursor protein. J Neurosci Res 75, 117-124. (Pubitemid 38049412)
98. Francis YI, Fa M, Ashraf H, Zhang H, Staniszewski A, Latchman DS, Arancio O (2009) Dysregulation of histone acetylation in the APP/PS1 mouse model of Alzheimer's disease. J Alzheimers Dis 18, 131-139.
99. Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt JD, Rumbaugh G (2010) Inhibitors of class 1 histone deacetylases reverse contextual memory deficits in a mouse model of Alzheimer's disease. Neuropsychopharmacology 35, 870-880.
100. Trollope AF, Gutierrez-Mecinas M, Mifsud KR, Collins A, Saunderson EA, Reul JM (2012) Stress, epigenetic control of gene expression and memory formation. Exp Neurol 233, 3-11.
101. Casati L, Sendra R, Colciago A, Negri-Cesi P, Berdasco M, Esteller M, Celotti F (2012) Polychlorinated biphenyls affect histone modification pattern in early development of rats: A role for androgen receptor-dependent modulation? Epigenomics 4, 101-112.
102. Arita A, Niu J, Qu Q, Zhao N, Ruan Y, Nadas A, Chervona Y, Wu F, Sun H, Hayes RB, Costa M (2012) Global levels of histone modifications in peripheral blood mononuclear cells of subjects with exposureto nickel. Environ Health Perspect 120, 198-203.
103. McKay JA, Mathers JC (2011) Diet induced epigenetic changes and their implications for health. Acta Physiol (Oxf) 202, 103-118.
104. Koseki T, Mouri A, Mamiya T, Aoyama Y, Toriumi K, Suzuki S, Nakajima A, Yamada T, Nagai T, Nabeshima T (2011) Exposure to enriched environments during adolescence prevents abnormal behaviours associated with histone deacetylationinphencyclidine-treated mice. IntJNeuropsy-chopharmacol, 1-13.
105. Fu C, Chute DJ, Farag ES, Garakian J, Cummings JL, Vin-ters HV (2004) Comorbidity in dementia: An autopsy study. Arch Pathol Lab Med 128, 32-38. (Pubitemid 38049563)
106. Bhat NR (2010) Linking cardiometabolic disorders to sporadic Alzheimer's disease: A perspective on potential mechanisms and mediators. J Neurochem 115, 551-562.
107. Profenno LA, Porsteinsson AP, Faraone SV (2010) Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry 67, 505-512.
108. Garcia-Lara JM, Aguilar-Navarro S, Gutierrez-Robledo LM, Avila-Funes JA (2010) The metabolic syndrome, diabetes, and Alzheimer's disease. Rev Invest Clin 62, 343-349.
109. Frisardi V, Solfrizzi V, Seripa D, Capurso C, Santam-ato A, Sancarlo D, Vendemiale G, Pilotto A, Panza F (2010) Metabolic-cognitive syndrome: A cross-talk between metabolic syndrome and Alzheimer's disease. Ageing Res Rev 9, 399-417.
110. Bruce KD, Cagampang FR (2011) Epigenetic priming of the metabolic syndrome. Toxicol Mech Methods 21, 353-361.
111. Farris W, Mansourian S, Leissring MA, Eckman EA, Bertram L, Eckman CB, Tanzi RE, Selkoe DJ (2004) Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. Am J Pathol 164, 1425-1434. (Pubitemid 38387808)
112. Lahiri DK, Maloney B, Zawia NH (2009) The LEARn model: An epigenetic explanation for idiopathic neurobi-ological diseases. Mol Psychiatry 14, 992-1003.
113. Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8, 253-262. (Pubitemid 46439287)
114. Heindel JJ, McAllister KA, Worth L Jr, Tyson FL (2006) Environmental epigenomics, imprinting and disease susceptibility. Epigenetics 1, 1-6.
115. 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 226, 1390-1398.
116. Plagemann A, Roepke K, Harder T, Brunn M, Harder A, Wittrock-Staar M, Ziska T, Schellong K, Rodekamp E, Melchior K, Dudenhausen JW (2010) Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding. J Perinat Med 38, 393-400.
117. Fujiki K, Kano F, Shiota K, Murata M (2009) Expression of the peroxisome proliferator activated receptor gamma gene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes. BMC Biol 7, 38.
118. Kolb H, Mandrup-Poulsen T (2010) The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation. Diabetologia 53, 10-20.
119. Movassagh M, Vujic A, Foo R (2011) Genome-wide DNA methylation inhumanheartfailure. Epigenomics3, 103-109.
120. Flowers E, Froelicher ES, Aouizerat BE (2011) Geneenvironment interactions in cardiovascular disease. Eur J Cardiovasc Nurs, doi: 10.1016/j.ejcnurse.2011.06.001.
121. Barker DJ, Eriksson JG, Forsen T, Osmond C (2002) Fetal origins of adult disease: Strength of effects and biological basis. Int J Epidemiol 31, 1235-1239. (Pubitemid 36204489)
122. Gluckman PD, Hanson MA, Beedle AS (2007) Early life events and their consequences for later disease:Alife history and evolutionary perspective. Am J Hum Biol 19, 1-19. (Pubitemid 46062455)
123. 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 overexpres-sion of amyloid precursor protein and beta-amyloid in the aging brain. J Neurosci 25, 823-829. (Pubitemid 40170996)
124. 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, 3-9.
125. Sayers EW, Barrett T, Benson DA, Bolton E, Bryant SH, Canese K, Chetvernin V, Church DM, DiCuccio M, Feder-hen S, Feolo M, Fingerman IM, Geer LY, Helmberg W, Kapustin Y, Landsman D, Lipman DJ, Lu Z, Madden TL, Madej T, Maglott DR, Marchler-Bauer A, Miller V, Mizrachi I, Ostell J, Panchenko A, Phan L, Pruitt KD, Schuler GD, Sequeira E, Sherry ST, Shumway M, Sirotkin K, Slotta D, Souvorov A, Starchenko G, Tatusova TA, Wagner L, Wang Y, Wilbur WJ, Yaschenko E, Ye J (2011) Database resources of the National Center for Biotechnology Infor mation. Nucleic Acids Res 39, D38-D51.
126. Kanvah S, Schuster GB (2005) The sacrificial role of easily oxidizable sites in the protection of DNA from damage. Nucleic Acids Res 33, 5133-5138. (Pubitemid 41487821)
127. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A 100, 4162-4167. (Pubitemid 36418174)
128. Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, van Leuven F, Heneka MT (2006) Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activa tion of PPARgamma. Proc Natl Acad Sci U S A 103, 443-448. (Pubitemid 43122420)
129. Sugii S, Evans RM (2011) Epigenetic codes of PPARgamma in metabolic disease. FEBS Lett 585, 2121-2128.
130. Goodarzi MO, Lehman DM, Taylor KD, Guo X, Cui J, Quinones MJ, Clee SM, Yandell BS, Blangero J, Hsueh WA, Attie AD, Stern MP, Rotter JI (2007) SORCS1: Anovel human type 2 diabetes susceptibility gene suggested by the mouse. Diabetes 56, 1922-1929. (Pubitemid 47025461)
131. Lane RF, Raines SM, Steele JW, Ehrlich ME, Lah JA, Small SA, Tanzi RE, Attie AD, Gandy S (2010) Diabetes-associated SorCS1 regulates Alzheimer's amyloid-beta metabolism: Evidence for involvement of SorL1 and the retromer complex. J Neurosci 30, 13110-13115.
132. Reitz C, Tokuhiro S, Clark LN, Conrad C, Vonsattel JP, Hazrati LN, Palotas A, Lantigua R, Medrano M, Jiménez-Velázquez I Z, Vardarajan B, Simkin I, Haines JL, Pericak-Vance MA, Farrer LA, Lee JH, Rogaeva E, George-Hyslop PS, Mayeux R (2011) SORCS1 alters amyloid precursor protein processing and variants may increase Alzheimer's disease risk. Ann Neurol 69, 47-64.
133. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Bur-dge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135, 1382-1386. (Pubitemid 40799599)
134. Chan A, Shea TB (2006) Supplementation with apple juice attenuates presenilin-1 overexpression during dietary and genetically-induced oxidative stress. J Alzheimers Dis 10, 353-358.
135. Rogers EJ, Milhalik S, Orthiz D, Shea TB (2004) Apple juice prevents oxidative stress and impaired cognitive performance causedby genetic and dietary deficienciesinmice. J Nutr Health Aging 8, 92-97. (Pubitemid 38374595)
136. Colin-Gonzalez AL, Ortiz-Plata A, Villeda-Hernandez J, Barrera D, Molina-Jijon E, Pedraza-Chaverri J, Maldonado PD (2011) Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats. Plant Foods Hum Nutr 66, 348-354.
137. Ray B, Chauhan NB, Lahiri DK (2011) The "aged garlic extract": (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD). Curr Med Chem 18, 3306-3313.
138. Demirkaya E, Avci A, Kesik V, Karslioglu Y, Oztas E, Kismet E, Gokcay E, Durak I, Koseoglu V (2009) Cardioprotective roles of aged garlic extract, grape seed proanthocyanidin, and hazelnut on doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol 87, 633-640.
139. Reuter S, Gupta SC, Park B, Goel A, Aggarwal BB (2011) Epigenetic changes
140. Yun JM, Jialal I, Devaraj S (2011) Epigenetic regulation of high glucose-induced proinflammatory cytokine production in monocytes by curcumin. J Nutr Biochem 22, 450-458.
141. Liu Z, Xie Z, Jones W, Pavlovicz RE, Liu S, Yu J, Li PK, Lin J, Fuchs JR, Marcucci G, Li C, Chan KK (2009) Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett 19, 706-709.
142. Langan RC, Zawistoski KJ (2011) Update on vitamin B12 deficiency. Am Fam Physician 83, 1425-1430.
143. van Dyck CH, Lyness JM, Rohrbaugh RM, Siegal AP (2009) Cognitive and psychiatric effects of vitamin B12 replacement in dementia with low serum B12 levels: A nursing home study. Int Psychogeriatr 21, 138-147.
144. Siuda J, Gorzkowska A, Patalong-Ogiewa M, Krzystanek E, Czech E, Wiechula B, Garczorz W, Danch A, Jasinska-Myga B, Opala G (2009) From mild cognitive impairment to Alzheimer's disease - influence of homocysteine, vitamin B12 and folate on cognition over time: Results from one-year follow-up. Neurol Neurochir Pol 43, 321-329.
145. Mayr E (1999) Systematics and the origin of species, from the viewpoint ofa zoologist, Harvard University Press, Cambridge, MA, USA, pp. 281-282.
146. Maseri A (2010) The tako-tsubo cardiomyopathy syndrome: Lumpers or splitters? J Cardiovasc Med (Hagerstown) 11, 402-403.
147. Shea V (2005) Lumpers, splitters, and Asperger syndrome. J Autism Dev Disord 35, 871-872.
148. Wittchen HU, Schuster P, Lieb R (2001) Comorbidity and mixed anxiety-depressive disorder: Clinical curiosity or pathophysiological need? Hum Psychopharmacol 16, S21-S30. (Pubitemid 32218892)
149. McKusick VA (1969) On lumpers and splitters, or the nosology of genetic disease. Perspect Biol Med 12, 298-312.
150. Wing L, Gould J, Gillberg C (2011) Autism spectrum disorders in the DSM-V: Better or worse than the DSM-IV? Res Dev Disabil 32, 768-773.
151. Brock B, Basha R, DiPalma K, Anderson A, Harry GJ, Rice DC, Maloney B, Lahiri DK, Zawia NH (2008) Co-localization and distribution of cerebral APP and SP1 and its relationship to amyloidogenesis. J Alzheimers Dis 13, 71-80. (Pubitemid 351365624)
152. Hoffman PW, Chernak JM (1995) DNA binding and regulatory effects of transcription factors SP1 and USF at the rat amyloid precursor protein gene promoter. Nucleic Acids Res 23, 2229-2235.
153. Lahiri DK, Maloney B (2010) The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps. Experimental Gerontology 45, 291-296.