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

Abstract

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 β-peptide (Aβ) production in AD. Mouse Neuro-2a cells expressing human APP695 were incubated with folic acid (2.8–40 μmol/L), and with or without zebularine (the DNMT inhibitor). DNMT activity, cell viability, Aβ 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 Aβ protein production, whereas inhibition of DNMT activity by zebularine increased Aβ production. The results indicate that folic acid induces methylation potential-dependent DNMT enzymes, thereby attenuating Aβ production.

Artificial Neural Networks Link One-Carbon Metabolism to Gene-Promoter Methylation in Alzheimer’s Disease

“…The present Auto-CM analysis also linked low hcy levels to high promoter methylation of genes required for DNA methylation reactions (DNMT1, DNMT3A, DNMT3B, and MTHFR), whilst low folates and advancing age were linked to their low methylation. So that, present results confirm previous cell culture studies revealing that folic acid can impact on DNA methylation levels through the modulation of proteins required for DNA methylation reactions [5][6][7]. Particularly, DNMT1 is required for the maintenance of DNA methylation patterns during development and cell division, whilst DNMT3a and DNMT3b are de novo methyltransferases that establish DNA methylation patterns during early development [21].…”

“…metabolism and gene-promoter methylation levels of the selected genes. Particularly, present data confirm previous in vitro and animal model results suggesting a link between dietary folates and related B-group vitamins and the methylation levels of genes required for Aβ production, such as PSEN1 and BACE1 [4][5][6][7]. PSEN1 codes for the presenilin 1 protein, involved in the γ-secretase cleavage of the amyloid-β protein precursor (AβPP), and is mutated in familial early-onset AD cases [16].…”

“…Within this context, we believe that the present observation of a connection between promoter methylation levels of a panel of genes and circulating levels of folate, vitamin B12 and hcy, coupled with similar evidence coming from previous in vitro or animal investigations [4][5][6][7], should stimulate novel questions in AD research to be addressed in future studies, including the following: 1) "Are the global methylation changes so far observed in DNA from AD brains and peripheral tissues related to the nutritional status, and particularly to the bioavailability of methyl donor compounds? "…”

“…Particularly, DNMT1 is required for the maintenance of DNA methylation patterns during development and cell division, whilst DNMT3a and DNMT3b are de novo methyltransferases that establish DNA methylation patterns during early development [21]. Studies in mouse neuronal cells have shown that folic acid stimulates DNMTs gene and protein expression, and DNMTs activities, but data in human LOAD patients are missing [5,6]. The MTHFR gene codes for methylenetetrahydrofolate reductase, a key protein for the inter-conversion of folate derivatives required for DNA methylation reactions, and MTHFR genetic polymorphisms have been associated to LOAD risk [22].…”

DNA Methylation in Neurodegenerative and Cerebrovascular Disorders

“…Indeed, the study of Francesco et al was performed only in patients with late-onset AD, and our study included different types of dementia in different stages of the disease. It has been also described that DNMT expression is also increased by folic acid, a crucial vitamin for the methylation process, in N2a-APP cells, and treatment with zebalurine, a DNMT inhibitor, increases Aβ production [67]. These results reinforce the important role that global methylation and DNMT expression may play in neurodegenerative diseases.…”