RT Journal Article SR Electronic T1 Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1752 OP 1762 DO 10.1523/JNEUROSCI.22-05-01752.2002 VO 22 IS 5 A1 Inna I. Kruman A1 T. S. Kumaravel A1 Althaf Lohani A1 Ward A. Pedersen A1 Roy G. Cutler A1 Yuri Kruman A1 Norman Haughey A1 Jaewon Lee A1 Michele Evans A1 Mark P. Mattson YR 2002 UL http://www.jneurosci.org/content/22/5/1752.abstract AB 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.