title: Folic Acid Alters Methylation Profile of JAK-STAT and Long-Term Depression Signaling Pathways in Alzheimer's Disease Models.
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.
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Xumei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, USA.
authors.forename: John X
authors.initials: JX
authors.lastname: Wilson
authors.affiliation: Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China. tjgwhuang@126.com.
authors.forename: Guowei
authors.initials: G
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D005492:Folic Acid / Q000494:pharmacology*; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008297:Male; D008822:Mice, Transgenic; D015203:Reproducibility of Results; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D050791:STAT Transcription Factors; D005492:Folic Acid; D053612:Janus Kinases
keywords: Alzheimer’s disease; DNA methylation profile; Folic acid; JAK-STAT signaling pathway; Long-term depression signaling pathway