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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1752-1762
Number of pages11
JournalJournal of Neuroscience
Volume22
Issue number5
StatePublished - Mar 1 2002
Externally publishedYes

Fingerprint

Folic Acid Deficiency
Homocysteine
Folic Acid
Amyloid
DNA Repair
Alzheimer Disease
Theoretical Models
DNA Damage
Neurons
Amyloid beta-Protein Precursor
Folic Acid Antagonists
Uracil
Methotrexate
Transgenic Mice
Cell Death
Carbon
Diet
DNA
Brain

Keywords

  • Apoptosis
  • Comet assay
  • Glycosylase
  • Oxidative stress
  • Transgenic
  • Uracil

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Kruman, I. I., Kumaravel, T. S., Lohani, A., Pedersen, W. A., Cutler, R. G., Kruman, Y., ... Mattson, M. P. (2002). Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. Journal of Neuroscience, 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. / Kruman, Inna I.; Kumaravel, T. S.; Lohani, Althaf; Pedersen, Ward A.; Cutler, Roy G.; Kruman, Yuri; Haughey, Norman; Lee, Jaewon; Evans, Michele; Mattson, Mark P.

In: Journal of Neuroscience, Vol. 22, No. 5, 01.03.2002, p. 1752-1762.

Research output: Contribution to journalArticle

Kruman, II, Kumaravel, TS, Lohani, A, Pedersen, WA, Cutler, RG, Kruman, Y, Haughey, N, Lee, J, Evans, M & Mattson, MP 2002, 'Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease', Journal of Neuroscience, vol. 22, no. 5, pp. 1752-1762.
Kruman, Inna I. ; Kumaravel, T. S. ; Lohani, Althaf ; Pedersen, Ward A. ; Cutler, Roy G. ; Kruman, Yuri ; Haughey, Norman ; Lee, Jaewon ; Evans, Michele ; Mattson, Mark P. / Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 5. pp. 1752-1762.
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