DNA Demethylation Upregulated Nrf2 Expression And Activity In Alzheimer’s Disease Celluar Model

Nuclear factor erythroid 2-related factor 2(Nrf2) is an important transcription factor in the defence against oxidative stress. Accumulating evidence has shown that oxidative stress plays a key role in pathogenesis of Alzheimer’s disease(AD). Previous animal and clinical studies had observed decreased brain level of Nrf2 in AD. However, the underlying regulation mechanisms of Nrf2 in AD remain largely elusive. Here, we used the DNA methyltransferases(Dnmts) inhibitor 5-aza-2′-deoxycytidine(5-aza-CdR) to test whether Nrf2 expression was regulated by methylation in N2 a cells characterizing by expressing human Swedish mutant amyloid precursor protein(N2a/APPswe). We found 5-aza-CdR treatment enabled increasing both Nrf2 mRNA and protein levels via repression the expression of Dnmts and thereby demethylation DNA. In addition,5-aza-CdR mediated upregulation of Nrf2 expression was concomitant with increased nuclear translocation of Nrf2 and higher expression of Nrf2 downstream target gene NAD(P)H:quinone oxidoreductas(NQO1). Taken together, our study showed that the demethylation enabled upregulation of Nrf2 levels and subsequently increased antioxidant gene, which may provide potential new directions for treatment of AD.