QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (194) Citing Articles via Google Scholar Google Scholar Articles by Kruman, I. I. Articles by Mattson, M. P. Search for Related Content PubMed PubMed Citation Articles by Kruman, I. I. Articles by Mattson, M. P.

 Previous Article  |  Next Article 

The Journal of Neuroscience, March 1, 2002, 22(5):1752-1762

Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease

Inna I. Kruman¹, T. S. Kumaravel², Althaf Lohani², Ward A. Pedersen¹, Roy G. Cutler¹, Yuri Kruman¹, Norman Haughey¹, Jaewon Lee¹, Michele Evans², and Mark P. Mattson^{1, 3}

Laboratories of ¹ Neurosciences and ² Cellular and Molecular Biology, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and ³ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid -peptide (A) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by A. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated A toxicity as the result of reduced repair of A-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of A were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by A.

Key words: apoptosis; comet assay; glycosylase; oxidative stress; transgenic; uracil

---

Copyright © 2002 Society for Neuroscience  0270-6474/02/2251752-11$05.00/0

This article has been cited by other articles:

				A. M. Troen, M. Shea-Budgell, B. Shukitt-Hale, D. E. Smith, J. Selhub, and I. H. Rosenberg B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice PNAS, August 26, 2008; 105(34): 12474 - 12479. [Abstract] [Full Text] [PDF]

				G. Kronenberg, C. Harms, R. W. Sobol, F. Cardozo-Pelaez, H. Linhart, B. Winter, M. Balkaya, K. Gertz, S. B. Gay, D. Cox, et al. Folate Deficiency Induces Neurodegeneration and Brain Dysfunction in Mice Lacking Uracil DNA Glycosylase J. Neurosci., July 9, 2008; 28(28): 7219 - 7230. [Abstract] [Full Text] [PDF]

				E. Szatmari, K. B. Kalita, G. Kharebava, and M. Hetman Role of Kinase Suppressor of Ras-1 in Neuronal Survival Signaling by Extracellular Signal-Regulated Kinase 1/2 J. Neurosci., October 17, 2007; 27(42): 11389 - 11400. [Abstract] [Full Text] [PDF]

				J. L. Cummings, R. Doody, and C. Clark Disease-modifying therapies for Alzheimer disease: Challenges to early intervention Neurology, October 16, 2007; 69(16): 1622 - 1634. [Abstract] [Full Text] [PDF]

				J. Kim, M. H. Park, E. Kim, C. Han, S. A. Jo, and I. Jo Plasma Homocysteine Is Associated with the Risk of Mild Cognitive Impairment in an Elderly Korean Population J. Nutr., September 1, 2007; 137(9): 2093 - 2097. [Abstract] [Full Text] [PDF]

				L. Weissman, D.-G. Jo, M. M. Sorensen, N. C. de Souza-Pinto, W. R. Markesbery, M. P. Mattson, and V. A. Bohr Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment Nucleic Acids Res., August 17, 2007; (2007) gkm605v1. [Abstract] [Full Text] [PDF]

				S. Mahabir, C. C Abnet, Y.-L. Qiao, L. D Ratnasinghe, S. M Dawsey, Z.-W. Dong, P. R Taylor, and S. D Mark A prospective study of polymorphisms of DNA repair genes XRCC1, XPD23 and APE/ref-1 and risk of stroke in Linxian, China J. Epidemiol. Community Health, August 1, 2007; 61(8): 737 - 741. [Abstract] [Full Text] [PDF]

				D. J. Culley, S. V. Raghavan, M. Waly, M. G. Baxter, R. Yukhananov, R. C. Deth, and G. Crosby Nitrous Oxide Decreases Cortical Methionine Synthase Transiently but Produces Lasting Memory Impairment in Aged Rats Anesth. Analg., July 1, 2007; 105(1): 83 - 88. [Abstract] [Full Text] [PDF]

				L.-K. Yang, K.-C. Wong, M.-Y. Wu, S.-L. Liao, C.-S. Kuo, and R.-F. S. Huang Correlations Between Folate, B12, Homocysteine Levels, and Radiological Markers of Neuropathology in Elderly Post-Stroke Patients J. Am. Coll. Nutr., June 1, 2007; 26(3): 272 - 278. [Abstract] [Full Text] [PDF]

				E. N. Rowan, H. O. Dickinson, S. Stephens, C. Ballard, R. Kalaria, and R. Anne Kenny Homocysteine and post-stroke cognitive decline Age Ageing, May 1, 2007; 36(3): 339 - 343. [Full Text] [PDF]

				D. Kirkland, M Aardema, N Banduhn, P Carmichael, R Fautz, J-R Meunier, and S Pfuhler In vitro approaches to develop weight of evidence (WoE) and mode of action (MoA) discussions with positive in vitro genotoxicity results Mutagenesis, May 1, 2007; 22(3): 161 - 175. [Abstract] [Full Text] [PDF]

				J. A. Luchsinger, M.-X. Tang, J. Miller, R. Green, and R. Mayeux Relation of Higher Folate Intake to Lower Risk of Alzheimer Disease in the Elderly Arch Neurol, January 1, 2007; 64(1): 86 - 92. [Abstract] [Full Text] [PDF]

				P. Thomas and M. Fenech A review of genome mutation and Alzheimer's disease Mutagenesis, January 1, 2007; 22(1): 15 - 33. [Abstract] [Full Text] [PDF]

				M. Tettamanti, M. T. Garri, A. Nobili, E. Riva, and U. Lucca Low Folate and the Risk of Cognitive and Functional Deficits in the Very Old: The Monzino 80-plus Study J. Am. Coll. Nutr., December 1, 2006; 25(6): 502 - 508. [Abstract] [Full Text] [PDF]

				S. M. Smith, S. A. Mathews Oliver, S. R. Zwart, G. Kala, P. A. Kelly, J. S. Goodwin, and C. B. Dyer Nutritional Status Is Altered in the Self-Neglecting Elderly J. Nutr., October 1, 2006; 136(10): 2534 - 2541. [Abstract] [Full Text] [PDF]

				H. Refsum, E. Nurk, A. D. Smith, P. M. Ueland, C. G. Gjesdal, I. Bjelland, A. Tverdal, G. S. Tell, O. Nygard, and S. E. Vollset The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease J. Nutr., June 1, 2006; 136(6): 1731S - 1740S. [Abstract] [Full Text] [PDF]

				C. Borek Garlic Reduces Dementia and Heart-Disease Risk J. Nutr., March 1, 2006; 136(3): 810S - 812S. [Abstract] [Full Text] [PDF]

				K Alagiakrishnan, P McCracken, and H Feldman Treating vascular risk factors and maintaining vascular health: Is this the way towards successful cognitive ageing and preventing cognitive decline? Postgrad. Med. J., February 1, 2006; 82(964): 101 - 105. [Abstract] [Full Text] [PDF]

				M. E. Gurol, M. C. Irizarry, E. E. Smith, S. Raju, R. Diaz-Arrastia, T. Bottiglieri, J. Rosand, J. H. Growdon, and S. M. Greenberg Plasma {beta}-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy Neurology, January 10, 2006; 66(1): 23 - 29. [Abstract] [Full Text] [PDF]

				M. C. Irizarry, M. E. Gurol, S. Raju, R. Diaz-Arrastia, J. J. Locascio, M. Tennis, B. T. Hyman, J. H. Growdon, S. M. Greenberg, and T. Bottiglieri Association of homocysteine with plasma amyloid {beta} protein in aging and neurodegenerative disease Neurology, November 8, 2005; 65(9): 1402 - 1408. [Abstract] [Full Text] [PDF]

				K. L Tucker, N. Qiao, T. Scott, I. Rosenberg, and A. Spiro III High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study Am. J. Clinical Nutrition, September 1, 2005; 82(3): 627 - 635. [Abstract] [Full Text] [PDF]

				G. Ravaglia, P. Forti, F. Maioli, M. Martelli, L. Servadei, N. Brunetti, E. Porcellini, and F. Licastro Homocysteine and folate as risk factors for dementia and Alzheimer disease Am. J. Clinical Nutrition, September 1, 2005; 82(3): 636 - 643. [Abstract] [Full Text] [PDF]

				H.-K. Kuo, F. A. Sorond, J.-H. Chen, A. Hashmi, W. P. Milberg, and L. A. Lipsitz The Role of Homocysteine in Multisystem Age-Related Problems: A Systematic Review J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2005; 60(9): 1190 - 1201. [Abstract] [Full Text] [PDF]

				G. Ravaglia, P. Forti, F. Maioli, N. Brunetti, M. Martelli, L. Servadei, L. Bastagli, M. Bianchin, and E. Mariani Serum C-Reactive Protein and Cognitive Function in Healthy Elderly Italian Community Dwellers J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2005; 60(8): 1017 - 1021. [Abstract] [Full Text] [PDF]

				M. Endres, M. Ahmadi, I. Kruman, D. Biniszkiewicz, A. Meisel, and K. Gertz Folate Deficiency Increases Postischemic Brain Injury Stroke, February 1, 2005; 36(2): 321 - 325. [Abstract] [Full Text] [PDF]

				T. M. Scott, K. L. Tucker, A. Bhadelia, B. Benjamin, S. Patz, R. Bhadelia, E. Liebson, L. L. Price, J. Griffith, I. Rosenberg, et al. Homocysteine and B Vitamins Relate to Brain Volume and White-Matter Changes in Geriatric Patients With Psychiatric Disorders Am J Geriatr Psychiatry, December 1, 2004; 12(6): 631 - 638. [Abstract] [Full Text] [PDF]

				I. I. Kruman, E. Schwartz, Y. Kruman, R. G. Cutler, X. Zhu, N. H. Greig, and M. P. Mattson Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis J. Biol. Chem., October 15, 2004; 279(42): 43952 - 43960. [Abstract] [Full Text] [PDF]

				R. B. Postuma and A. E. Lang Homocysteine and levodopa: Should Parkinson disease patients receive preventative therapy? Neurology, September 14, 2004; 63(5): 886 - 891. [Abstract] [Full Text] [PDF]

				D. C. Cabelof, J. J. Raffoul, J. Nakamura, D. Kapoor, H. Abdalla, and A. R. Heydari Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase {beta} Haploinsufficiency J. Biol. Chem., August 27, 2004; 279(35): 36504 - 36513. [Abstract] [Full Text] [PDF]

				H. Chen, S. M. Zhang, M. A. Schwarzschild, M. A. Hernan, G. Logroscino, W. C. Willett, and A. Ascherio Folate Intake and Risk of Parkinson's Disease Am. J. Epidemiol., August 15, 2004; 160(4): 368 - 375. [Abstract] [Full Text] [PDF]

				G. Ravaglia, P. Forti, F. Maioli, G. Bianchi, M. Martelli, T. Talerico, L. Servadei, M. Zoli, and E. Mariani Plasma amino acid concentrations in patients with amnestic mild cognitive impairment or Alzheimer disease Am. J. Clinical Nutrition, August 1, 2004; 80(2): 483 - 488. [Abstract] [Full Text] [PDF]

				P. Quadri, C. Fragiacomo, R. Pezzati, E. Zanda, G. Forloni, M. Tettamanti, and U. Lucca Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia Am. J. Clinical Nutrition, July 1, 2004; 80(1): 114 - 122. [Abstract] [Full Text] [PDF]

				K. N. Maclean, E. Kraus, and J. P. Kraus The Dominant Role of Sp1 in Regulating the Cystathionine {beta}-Synthase -1a and -1b Promoters Facilitates Potential Tissue-specific Regulation by Kruppel-like Factors J. Biol. Chem., March 5, 2004; 279(10): 8558 - 8566. [Abstract] [Full Text] [PDF]

				M. P. Mattson Gene-Diet Interactions in Brain Aging and Neurodegenerative Disorders Ann Intern Med, September 2, 2003; 139(5_Part_2): 441 - 444. [Abstract] [Full Text] [PDF]

				N. V. Oleinik and S. A. Krupenko Ectopic Expression of 10-Formyltetrahydrofolate Dehydrogenase in A549 Cells Induces G1 Cell Cycle Arrest and Apoptosis Mol. Cancer Res., June 1, 2003; 1(8): 577 - 588. [Abstract] [Full Text] [PDF]

				P. S. Aisen, S. Egelko, H. Andrews, R. Diaz-Arrastia, M. Weiner, C. DeCarli, W. Jagust, J. W. Miller, R. Green, K. Bell, et al. A Pilot Study of Vitamins to Lower Plasma Homocysteine Levels in Alzheimer Disease Am J Geriatr Psychiatry, April 1, 2003; 11(2): 246 - 249. [Abstract] [Full Text] [PDF]

				G. Ravaglia, P. Forti, F. Maioli, A. Muscari, L. Sacchetti, G. Arnone, V. Nativio, T. Talerico, and E. Mariani Homocysteine and cognitive function in healthy elderly community dwellers in Italy Am. J. Clinical Nutrition, March 1, 2003; 77(3): 668 - 673. [Abstract] [Full Text] [PDF]

				M. P. Mattson Will caloric restriction and folate protect against AD and PD? Neurology, February 25, 2003; 60(4): 690 - 695. [Abstract] [Full Text] [PDF]

				J.-m. Kim, H. Lee, and N. Chang Hyperhomocysteinemia Due to Short-Term Folate Deprivation Is Related to Electron Microscopic Changes in the Rat Brain J. Nutr., November 1, 2002; 132(11): 3418 - 3421. [Abstract] [Full Text] [PDF]

				P. Bruni, G. Minopoli, T. Brancaccio, M. Napolitano, R. Faraonio, N. Zambrano, U. Hansen, and T. Russo Fe65, a Ligand of the Alzheimer's beta -Amyloid Precursor Protein, Blocks Cell Cycle Progression by Down-regulating Thymidylate Synthase Expression J. Biol. Chem., September 13, 2002; 277(38): 35481 - 35488. [Abstract] [Full Text] [PDF]

				T. D. Stein and J. A. Johnson Lack of Neurodegeneration in Transgenic Mice Overexpressing Mutant Amyloid Precursor Protein Is Associated with Increased Levels of Transthyretin and the Activation of Cell Survival Pathways J. Neurosci., September 1, 2002; 22(17): 7380 - 7388. [Abstract] [Full Text] [PDF]

				M. P. Mattson, S. L. Chan, and W. Duan Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior Physiol Rev, July 1, 2002; 82(3): 637 - 672. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help