S-adenosylmethionine reduces the inhibitory effect of Aβ on BDNF expression through decreasing methylation level of BDNF exon ⠣ in rats

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-β (Aβ) intrahippocampal 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 Aβ. We found that Aβ 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 Aβ 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 Aβ or SAM, and further support the view of specific epigenetic modifications of a certain BDNF gene transcript.