Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor in the defense against oxidative stress. Cumulative evidence has shown that oxidative stress plays a key role in the pathogenesis of Alzheimer’s disease (AD). Previous animal and clinical studies had observed decreased expression of Nrf2 in AD. However, the underlying regulation mechanisms of Nrf2 in AD remain unclear. Here, we used the DNA methyltransferases (Dnmts) inhibitor 5-aza-2′-deoxycytidine (5-Aza) to test whether Nrf2 expression was regulated by methylation in N2a cells characterizing by expressing human Swedish mutant amyloid precursor protein (N2a/APPswe). We found 5-Aza treatment increased Nrf2 at both messenger RNA and protein levels via downregulating the expression of Dnmts and DNA demethylation. In addition, 5-Aza-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). Our study showed that DNA demethylation promoted the Nrf2 cell signaling pathway, which may enhance the antioxidant system against AD development.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative neurological disorder characterized pathologically by senile plaques, neurofibrillary tangles, and massive neuronal loss in the brain (Kumar et al, 2015)
By using the N2a/APPswe cell lines characterized by oxidative stress injury, we found Nuclear factor erythroid 2-related factor 2 (Nrf2) expression is regulated by DNA methylation. 5-Aza treatment can lead to the increase in the messenger RNA (mRNA) and protein expressions of the Nrf2 gene
Our results suggest that the first five CpG sites in the promoter may play an important role in Nrf2 expression via an epigenetic regulation of DNA methylation in AD cellular model
Summary
Alzheimer’s disease (AD) is a common neurodegenerative neurological disorder characterized pathologically by senile plaques, neurofibrillary tangles, and massive neuronal loss in the brain (Kumar et al, 2015). Numerous s1tudies have indicated that oxidative stress, an imbalance between free radicals and the antioxidant system, plays a significant role in the onset and progression of AD (Sultana et al, 2006; Zhao and Zhao, 2013). It has been reported that markers of oxidative stress were increased in the brains of AD patients (Williams et al, 2006). Because of the high concentration of polyunsaturated fatty acids and high oxygen consumptions in AD patients, those diseased brains were even more sensitive to oxidative stress (Farooqui and Horrocks, 1998). Reducing oxidative damage in the brains could be a legitimate target for effective AD therapy
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