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

• Published in: Molecular neurobiology Vol. 53; no. 9; pp. 6548 - 6556
• Main Authors: Li, Wen, Liu, Huan, Yu, Min, Zhang, Xumei, Zhang, Yan, Liu, Hongbo, Wilson, John X., Huang, Guowei
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2016; Springer Nature B.V
• Subjects: Alzheimer Disease - genetics; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Cell Biology; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; DNA methylation; DNA Methylation - drug effects; Epigenetics; Folic Acid - pharmacology; Humans; Janus Kinases - metabolism; Long-Term Synaptic Depression - drug effects; Male; Mice, Transgenic; Neurobiology; Neurology; Neurosciences; Reproducibility of Results; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; STAT Transcription Factors - metabolism; Vitamin B; Long-term depression signaling pathway; DNA methylation profile; Alzheimer’s disease; Folic acid; JAK-STAT signaling pathway
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-015-9556-9

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.