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

Wen Li,Mingyue Jiang,Xumei Zhang,John Wilson,Guowei Huang,Shijing Zhao,Huan Liu

doi:10.3390/ijms161025002

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.

Highlights

Alzheimer’s disease (AD) is one of the major amyloidoses, with two types of amyloid deposited in the brain: (i) amyloid β-peptide (Aβ) forming aggregates senile plaques and cerebrovascular amyloid angiopathy [1]; and (ii) tau protein, which forms neurofibrillary tangles, neuropil threads, and dystrophic neurites [2]
High expression of Aβ production due to the stable expression of human APP695 was seen in N2a-amyloid precursor protein (APP) cells (Figure 1)
Aβ was detected by immunofluorescence staining, nucleus staining by DAPI. (A) Representative images showing Aβ immunofluorescence; (B) Summary of Aβ production levels shows mean ± SEM for integrated optical density (IOD) of immunoreactive Aβ in 3 experiments

Summary

Introduction

Alzheimer’s disease (AD) is one of the major amyloidoses, with two types of amyloid deposited in the brain: (i) amyloid β-peptide (Aβ) forming aggregates senile plaques and cerebrovascular amyloid angiopathy [1]; and (ii) tau protein, which forms neurofibrillary tangles, neuropil threads, and dystrophic neurites [2]. The epigenetic mechanism of gene methylation provides a putative link between nutrition, one-carbon metabolism and disease progression, because dietary deficiency in transmethylation micronutrients (e.g., folate) may cause hypomethylation of promoter regions in AD-relevant genes. This effect is observed in AD models, for example in TgCRND8 mice which carrying mutant amyloid precursor protein (APP), fed a diet deficient in three kinds of vitamin B (folate, vitamin B12 and B6) [5]. The diet inhibits the metabolism of homocysteine by transsulfuration and remethylation pathways in

Results

Discussion

Conclusion