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Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells

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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Alzheimer’s disease (AD) is a highly prevalent type of dementia. The epigenetic mechanism of gene methylation provides a putative link between nutrition, one-carbon metabolism, and disease progression because folate deficiency may cause hypomethylation of promoter regions in AD-relevant genes. We hypothesized that folic acid supplementation may protect neuron cells from amyloid β (Aβ) oligomer-induced toxicity by modulating DNA methylation of APP and PS1 in AD models.

Methods

Primary hippocampal neuronal cells and hippocampal HT-22 cells were incubated for 24 h with a combination of folic acid and either Aβ oligomers or vehicle and were then incubated for 72 h with various concentrations of folic acid. AD transgenic mice were fed either folate-deficient or control diets and gavaged daily with various doses of folic acid (0 or 600 μg/kg). DNA methyltransferase (DNMT) activity, cell viability, methylation potential of cells, APP and PS1 expression, and the methylation of the respective promoters were determined.

Results

Aβ oligomers lowered DNMT activity, increased PS1 and APP expression, and decreased cell viability. Folic acid dose-dependently stimulated methylation potential and DNMT activity, altered PS1 and APP promoter methylation, decreased PS1 and APP expression, and partially preserved cell viability. Folic acid increased PS1 and APP promoter methylation in AD transgenic mice.

Conclusion

These results suggest a mechanism by which folic acid may prevent Aβ oligomer-induced neuronal toxicity.

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Abbreviations

Aβ:

Amyloid β-peptide

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

CBS:

Cystathionine-beta-synthase

DMEM:

Dulbecco’s Modified Eagle’s Medium

DNMT:

DNA methyltransferase

FBS:

Fetal bovine serum

OD:

Optical density

PBS:

Phosphate-buffered saline

PS:

Presenilin

SAH:

S-adenosylhomocysteine

SAM:

S-adenosylmethionine

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Acknowledgments

The authors state that they have nothing to disclose, and that there are no potential conflicts of interest. This research was supported by grants from the National Natural Science Foundation of China (Nos. 81130053 and 81202200). The authors’ responsibilities were as follows—G. Huang: planned experiments; H. Liu, S. Zhao, X. Zhang: performed experiments; W. Li, M. Zhang, Y. Xiao: analyzed data; H. Liu, W. Li, J.X. Wilson: wrote the paper.

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    Authors and Affiliations

    1. Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China

      Huan Liu, Wen Li, Shijing Zhao, Xumei Zhang, Meilin Zhang, Yanyu Xiao & Guowei Huang

    2. Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA

      John X. Wilson

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    1. Huan Liu
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    2. Wen Li
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    3. Shijing Zhao
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    5. Meilin Zhang
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    6. Yanyu Xiao
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    7. John X. Wilson
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    8. Guowei Huang
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    Corresponding author

    Correspondence to Guowei Huang.

    Additional information

    Huan Liu and Wen Li contributed equally to this work.

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    Liu, H., Li, W., Zhao, S. et al. Folic acid attenuates the effects of amyloid β oligomers on DNA methylation in neuronal cells. Eur J Nutr 55, 1849–1862 (2016). https://doi.org/10.1007/s00394-015-1002-2

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    • DOI: https://doi.org/10.1007/s00394-015-1002-2

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