Li Jingna, Wang Shanshan, Zhang Simiao, Cheng Dan, Yang Xiaopeng, Wang Yutong, Yin Honglei, Liu Yajun, Liu Yanqiu, Bai Hongying, Geng Shuang, Wang Yunliang
Department of Neurology, Second Affiliated Hospital of Zhengzhou University Zhengzhou 450014, Henan, China.
Department of Neurology, 960 Hospital of PLA Zibo 255300, Shandong, China.
Am J Transl Res. 2021 Dec 15;13(12):13380-13393. eCollection 2021.
Disturbance of mitochondrial proteins by amyloid beta-protein (Aβ) that associates with mitochondrial stress responses (MSR) is one of the pathological mechanisms of Alzheimer's disease (AD). This study tried to explore whether the axis of Jumonji domain-containing protein 3 (JMJD3)-trimethylated lysine 27 on histone H3 (H3K27me3)-brain derived neurotrophic factor (BDNF) is involved in the regulation of MSR which in turn intervenes in the process of AD, and whether curcumin (CUR) has a protective role against AD by influencing this axis, aiming to provide insights into AD treatment. AD mouse models presented a significant aggregation of Aβ, with conspicuous pathological changes in brain tissues and an increase in neuronal apoptosis. Moreover, the mRNA and protein levels of JMJD3 and BDNF were down-regulated, H3K27me3 methylation levels were increased, and the MSR markers (ClpP, HSP6, HSP-60, and ATFS-1) showed abnormal alterations. In cellular models of AD, up-regulation of either JMJD3 or BDNF up-regulated BDNF levels, down-regulated H3K27me3 methylation levels, mitigated abnormalities of MSR markers and Aβ aggregation, and increased cell proliferation and inhibited apoptosis. JMJD3 was confirmed to regulate Aβ and MSR via BDNF. In addition, CUR was confirmed to modulate JMJD3-H3K27me3-BDNF axis. Furthermore, moderate and high doses of CUR could improve the morphology and histopathology of the brain, inhibit Aβ aggregation and cell apoptosis, and maintain MSR balance at least partly by modulating the JMJD3-H3K27me3-BDNF axis. To sum up, moderate and high doses of CUR regulate the progression of AD via MSR JMJD3-H3K27me3-BDNF axis.
与线粒体应激反应（MSR）相关的淀粉样β蛋白（Aβ）对线粒体蛋白的干扰是阿尔茨海默病（AD）的病理机制之一。本研究试图探讨含Jumonji结构域蛋白3（JMJD3）-组蛋白H3上的三甲基化赖氨酸27（H3K27me3）-脑源性神经营养因子（BDNF）轴是否参与MSR的调节，进而干预AD进程，以及姜黄素（CUR）是否通过影响该轴对AD具有保护作用，旨在为AD治疗提供思路。AD小鼠模型出现Aβ显著聚集，脑组织有明显病理变化，神经元凋亡增加。此外，JMJD3和BDNF的mRNA及蛋白水平下调，H3K27me3甲基化水平升高，MSR标志物（ClpP、HSP6、HSP-60和ATFS-1）出现异常改变。在AD细胞模型中，上调JMJD3或BDNF均可上调BDNF水平，下调H3K27me3甲基化水平，减轻MSR标志物异常和Aβ聚集，并增加细胞增殖和抑制凋亡。证实JMJD3通过BDNF调节Aβ和MSR。此外，证实CUR可调节JMJD3-H3K27me3-BDNF轴。此外，中、高剂量CUR可改善脑形态和组织病理学，抑制Aβ聚集和细胞凋亡，并至少部分通过调节JMJD3-H3K27me3-BDNF轴维持MSR平衡。综上所述，中、高剂量CUR通过MSR JMJD3-H3K27me3-BDNF轴调节AD进程。
