Wang Peng, Wang Xiaoxuan, Qiao Ke, Zhang Yu, Nie Qian, Cui Jing, Sun Jing, Li Liang
Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Department of Pathology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Neurosci Lett. 2023 Mar 16;799:137118. doi: 10.1016/j.neulet.2023.137118. Epub 2023 Feb 9.
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.
淀粉样β蛋白（Aβ）诱导的氧化应激被认为是阿尔茨海默病（AD）发病的重要机制之一。AD患者大脑中内源性抗氧化剂Nrf2信号的抑制会加重氧化损伤，然而，Nrf2信号抑制的原因尚不清楚。据报道，小泛素样修饰（SUMO化）参与氧化损伤过程。为了研究SUMO化是否以及如何参与Aβ诱导的Nrf2信号通路抑制，本研究采用了Aβ海马内注射大鼠模型和Aβ处理的SH-SY5Y细胞模型。使用小干扰RNA和慢病毒转染干预SUMO化，并通过免疫沉淀评估SUMO化水平。目前的体内和体外研究表明，长期Aβ损伤下，Nrf2和MafF的SUMO化水平以及总体SUMO化水平均降低。同时，Nrf2与MafF的结合减少，伴随着与基因抗氧化反应元件（ARE）区域的低相互作用。SUMO蛋白的下调加剧了Aβ诱导的Nrf2信号通路抑制，而通过过表达Ubc9增强Nrf2和MafF的SUMO化则逆转了这一过程。这些结果表明，Aβ诱导的SUMO化减少导致了Nrf2信号的抑制，SUMO化可能是AD的一个潜在治疗靶点。
