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ARTICLE, Cellular/Molecular

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. Kruman, T. S. Kumaravel, Althaf Lohani, Ward A. Pedersen, Roy G. Cutler, Yuri Kruman, Norman Haughey, Jaewon Lee, Michele Evans and Mark P. Mattson
Journal of Neuroscience 1 March 2002, 22 (5) 1752-1762; DOI: https://doi.org/10.1523/JNEUROSCI.22-05-01752.2002
Inna I. Kruman
1Laboratories of Neurosciences and
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T. S. Kumaravel
2Cellular and Molecular Biology, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and
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Althaf Lohani
2Cellular and Molecular Biology, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and
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Ward A. Pedersen
1Laboratories of Neurosciences and
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Roy G. Cutler
1Laboratories of Neurosciences and
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Yuri Kruman
1Laboratories of Neurosciences and
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Norman Haughey
1Laboratories of Neurosciences and
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Jaewon Lee
1Laboratories of Neurosciences and
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Michele Evans
2Cellular and Molecular Biology, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, and
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Mark P. Mattson
1Laboratories of Neurosciences and
3Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
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Abstract

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 β-peptide (Aβ) 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 Aβ. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Aβ toxicity as the result of reduced repair of Aβ-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 Aβ 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 Aβ.

  • apoptosis
  • comet assay
  • glycosylase
  • oxidative stress
  • transgenic
  • uracil
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The Journal of Neuroscience: 22 (5)
Journal of Neuroscience
Vol. 22, Issue 5
1 Mar 2002
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Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease
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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. Kruman, T. S. Kumaravel, Althaf Lohani, Ward A. Pedersen, Roy G. Cutler, Yuri Kruman, Norman Haughey, Jaewon Lee, Michele Evans, Mark P. Mattson
Journal of Neuroscience 1 March 2002, 22 (5) 1752-1762; DOI: 10.1523/JNEUROSCI.22-05-01752.2002

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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. Kruman, T. S. Kumaravel, Althaf Lohani, Ward A. Pedersen, Roy G. Cutler, Yuri Kruman, Norman Haughey, Jaewon Lee, Michele Evans, Mark P. Mattson
Journal of Neuroscience 1 March 2002, 22 (5) 1752-1762; DOI: 10.1523/JNEUROSCI.22-05-01752.2002
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Keywords

  • apoptosis
  • comet assay
  • glycosylase
  • oxidative stress
  • transgenic
  • uracil

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