The structure of brain-derived neurotrophic factor (BDNF) gene is complex, which is composed of eight non-coding exons and one coding exon, each of them has its own unique promoter. Multiple BDNF transcripts have distinct functional properties and epigenetic modulation of BDNF gene transcription is implicated in the neurological disorders. In the present study, rat models with amyloid-beta (A beta) intra-hippocampal injection and PC12 cells were used to explore the role of DNA methylation in the promoters of BDNF exon IV and exon VI in BDNF suppression caused by A beta. We found that A beta inhibited BDNF expression accompanying with hypermethylation in BDNF exon IV promoter, meanwhile, S-adenosylmethionine (SAM), primary methyl donor, reversed the low BDNF expression through demethylation in BDNF exon IV promoter. No methylation change was observed in BDNF exon VI promoter. The alteration of DNA methylation caused by A beta or SAM was mediated by DNA methyltransferase 3A (DNMT3A). These data suggest that methylation change in BDNF exon IV is involved in the regulation of BDNF expression by A beta or SAM, and further support the view of specific epigenetic modifications of a certain BDNF gene transcript. (C) 2018 Elsevier Inc. All rights reserved.