Reduced SUMOylation of Nrf2 signaling contributes to its inhibition induced by amyloid-β.

Oxidative stress induced by amyloid-β (Aβ) has been considered as one of the important mechanisms in the development of Alzheimer disease (AD). The inhibition of endogenous antioxidant Nrf2 signaling in the brain of AD patients aggravates the oxidative damage, however, the causes of Nrf2 signaling inhibition are unclear. It is reported that smallubiquitin-like modification (SUMOylation) is involved in the process of oxidative injury. To investigate whether and how SUMOylation was involved in the inhibition of Nrf2 signaling pathway induced by Aβ, Aβ intrahippocampal injection rat model and Aβ treated SH-SY5Y cell model were used in the current study. Small interfering RNA and lentivirus transfection were used to intervene SUMOylation, and the level of SUMOylation was assessed by immunoprecipitation. The present in vivo and in vitro studies revealed that SUMOylation levels of Nrf2 and MafF, as well as the overall SUMOylation level were reduced under long-term Aβ insult. Meanwhile, the binding of Nrf2 to MafF was decreased, accompanied by low interaction with antioxidant response element (ARE) area of gene. Down-regulation of SUMO protein exacerbated the Aβ-induced inhibition of Nrf2 signaling pathway, while, enhancement of SUMOylation of Nrf2 and MafF by overexpression of Ubc9 reversed this process. These results imply that reduction in SUMOylation induced by Aβ contributed to the inhibition of Nrf2 signaling, and SUMOylation might be a potential therapeutic target of AD.