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Folic Acid Alters Methylation Profile of JAK-STAT and Long-Term Depression Signaling Pathways in Alzheimer’s Disease Models

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Abstract

Dementia has emerged as a major societal issue because of the worldwide aging population and the absence of any effective treatment. DNA methylation is an epigenetic mechanism that evidently plays a role in Alzheimer’s disease (AD). Folate acts through one-carbon metabolism to support the methylation of multiple substrates including DNA. We aimed to test the hypothesis that folic acid supplementation alters DNA methylation profiles in AD models. Mouse Neuro-2a cells expressing human APP695 (N2a-APP cells) were incubated with folic acid (2.8–20 μmol/L). AD transgenic mice were fed either folate-deficient or control diets and gavaged daily with water or folic acid (600 μg/kg). Gene methylation profiles were determined by methylated DNA immunoprecipitation-DNA microarray (MeDIP-chip). Differentially methylated regions (DMRs) were determined by Quantitative Differentially Methylated Regions analysis, and differentially methylated genes (DMGs) carrying at least three DMRs were selected for pathway analysis. Folic acid up-regulated DNA methylation levels in N2a-APP cells and AD transgenic mouse brains. Functional network analysis of folic acid-induced DMGs in these AD models revealed subnetworks composed of 24 focus genes in the janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and 12 focus genes in the long-term depression (LTD) signaling pathway. In conclusion, these results revealed a role for folic acid in the JAK-STAT and LTD signaling pathways which may be relevant to AD pathogenesis. This novel finding may stimulate reinvestigation of folic acid supplementation as a prophylactic or therapeutic treatment for AD.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

APP/PS1 mice:

The mice with APPswe/PS1ΔE9 mutations

BATMAN:

Bayesian tool for methylation analysis

CREB:

cAMP response element binding protein

DMEM:

Dulbecco’s modified Eagle’s medium

DMG:

Differentially methylated gene

DMR:

Differentially methylated region

DMROI:

Differentially methylated region of interest

FA:

Folic acid

JAK-STAT:

Janus kinase-signal transducer and activator of transcription

LTD:

Long-term depression

MeDIP-chip:

Methylated DNA immunoprecipitation-DNA microarray

N2a-APP:

N2a neuroblastoma cells overexpressing APP695

ROI:

Region of interest

TSS:

Transcription start site

TTS:

Transcription termination site

UMROI:

Undifferentially methylated region of interest

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Acknowledgments

This work was supported by a grant from the National Natural Science Foundation of China (No. 81130053).

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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

    Wen Li, Huan Liu, Min Yu, Xumei Zhang & Guowei Huang

  2. School of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China

    Yan Zhang & Hongbo Liu

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

    John X. Wilson

Authors
  1. Wen Li
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  2. Huan Liu
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  3. Min Yu
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  4. Xumei Zhang
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  5. Yan Zhang
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  6. Hongbo Liu
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  7. John X. Wilson
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  8. Guowei Huang
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Correspondence to Guowei Huang.

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The authors state that they have nothing to disclose and that there are no potential conflicts of interest.

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Supported by the National Natural Science Foundation of China. (No. 81130053).

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Li, W., Liu, H., Yu, M. et al. Folic Acid Alters Methylation Profile of JAK-STAT and Long-Term Depression Signaling Pathways in Alzheimer’s Disease Models. Mol Neurobiol 53, 6548–6556 (2016). https://doi.org/10.1007/s12035-015-9556-9

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  • DOI: https://doi.org/10.1007/s12035-015-9556-9

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