Folic Acid Inhibits Amyloid β-Peptide Production through Modulating DNA Methyltransferase Activity in N2a-APP Cells

Alzheimer's disease (AD) is a common neurodegenerative disease resulting in progressive dementia, and is a principal cause of dementia among older adults. Folate acts through one-carbon metabolism to support the methylation of multiple substrates. We hypothesized that folic acid supplementation modulates DNA methyltransferase (DNMT) activity and may alter amyloid -peptide (A) production in AD. Mouse Neuro-2a cells expressing human APP695 were incubated with folic acid (2.8-40 mol/L), and with or without zebularine (the DNMT inhibitor). DNMT activity, cell viability, A and DNMTs expression were then examined. The results showed that folic acid stimulated DNMT gene and protein expression, and DNMT activity. Furthermore, folic acid decreased A protein production, whereas inhibition of DNMT activity by zebularine increased A production. The results indicate that folic acid induces methylation potential-dependent DNMT enzymes, thereby attenuating A production.