S-Adenosylhomocysteine enhances DNA damage through increased β-amyloid formation and inhibition of the DNA-repair enzyme OGG1b in microglial BV-2 cells

S-Adenosylhomocysteine (SAH) is a risk factor for neurodegenerative diseases such as Alzheimer's disease, for which β-Amyliod (Aβ) formation is a major risk factor. We recently showed that SAH increases Aβ formation in mouse microglial BV2 cells. Here, we show that incubation of BV2 cells with SAH (0–500 nM) for 6–24 h sequentially increased Aβ formation, ROS and DNA damage measured as 8-oxo-deoxyguanosine (8-oxo-dG) levels. Pre-incubation of BV2 cells with 20 μM β-secretase inhibitor IV for 30 min followed by incubation with SAH (500 nM) markedly decreased Aβ formation and 8-oxo-dG levels. Treatment with SAH for 24 h concentration-dependently inhibited DNA methyltransferase (DNMT1) activity and inhibited DNMT1 binding to Sp1 site of 8-oxoG-DNA glycosylases I (OGG1) promoter and OGG1 protein and mRNA expression at 24 h; the latter effect was attributed to hypomethylation of the OGG1 gene promoter, because pre-incubation of cells with betaine (1.0 mM for 30 min) markedly prevented the inhibition of OGG1 protein expression induced by SAH. Overall, we demonstrate that SAH increases DNA damage in BV-2 cells possible by increased Aβ formation leading to increased formation of ROS. Furthermore, the DNA damage is enhanced by SAH through inhibition of DNMT1 activity and hypomethylation of OGG1 gene promoter.

► We demonstrate for the first time that S-adenosylhomocyeteine (SAH), a derivative of homocysteine and a key intermediate of methionine metabolism, markedly enhances DNA damage in BV-2 microglial cells. ► SAH exerts this effect through increased β-amyloid formation and hypomethylation of OGG1 gene in BV2 microglial cells via inhibition of DNMT1 binding to OGG1 promoter, leading to decreased DNA repair ability. ► Importantly, SAH elicits this effect at nanomolar concentrations which are comparable to the plasma SAH levels (10–500 nM) in humans.