Folic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice

Alzheimer's disease (AD) is associated with malnutrition, altered one-carbon metabolism and increased hippocampal amyloid-D peptide (AD) accumulation. Aberrant DNA methylation may be an epigenetic mechanism that underlies AD pathogenesis. We hypothesized that folic acid acts through an epigenetic gene silencing mechanism to lower AD levels in the APP/PSI transgenic mouse model of AD. APP/PSI mice were fed either folate-deficient or control diets and gavaged daily with 120 mu g/kg folic acid, 13.3 mg/kg S-adenosylmethionine (SAM) or both. Examination of the mice after 60 days of treatment showed that serum folate concentration increased with intake of folic acid but not SAM. Folate deficiency lowered endogenous SAM concentration, whereas neither intervention altered S-adenosylhomocysteine concentration. DNA methyltransferase (DNMT) activity increased with intake of folic acid raised DNMT activity in folate-deficient mice. DNA methylation rate was stimulated by folic acid in the amyloid precursor protein (APP) promoter and in the presenilin 1 (PSI) promoter. Folate deficiency elevated hippocampal APP, PSI and AD protein levels, and these rises were prevented by folic acid. In conclusion, these findings are consistent with a mechanism in which folic acid increases methylation potential and DNMT activity, modifies DNA methylation and ultimately decreases APP, PSI and AD protein levels. (C) 2015 Elsevier Inc. All rights reserved.