Format

Send to

Choose Destination
Mol Neurobiol. 2016 Nov;53(9):6548-6556. doi: 10.1007/s12035-015-9556-9. Epub 2015 Dec 1.

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

Author information

1
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
2
School of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
3
Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
4
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China. tjgwhuang@126.com.

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.

KEYWORDS:

Alzheimer’s disease; DNA methylation profile; Folic acid; JAK-STAT signaling pathway; Long-term depression signaling pathway

PMID:
26627706
DOI:
10.1007/s12035-015-9556-9
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center