姜黄素介导JMJD3对阿尔茨海默病的保护作用  

Protective effect of JMJD3 on Alzheimer's disease mediated by curcumin

作　　者：刘艳秋[1] 李静娜 王姗姗 张斯淼 程丹 尹红蕾 刘亚君 王运良 LIU Yan-qiu;LI Jing-na;WANG Shan-shan;ZHANG Si-miao;CHENG Dan;YIN Hong-lei;LIU Ya-jun;WANG Yun-liang(Department of Neurology,960th Hospital of thejoint logistics supportfarce of PLA,Zibo,Shandong 255300,China;Department of Neurology,the Second Affiliated Hospital of Zhengzhou University,Zhengzhou,Henan 450014,China)

机构地区：[1]中国人民解放军联勤保障部队第960医院神经内科,山东淄博255300 [2]郑州大学第二附属医院神经内科,河南郑州450014

出　　处：《阿尔茨海默病及相关病杂志》2022年第2期119-129,共11页Chinese Journal of Alzheimer's Disease and Related Disorders

基　　金：山东省自然科学基金(ZR2019MH065)。

摘　　要：目的:分析阿尔茨海默病(Alzheimer’s disease,AD)病理机制线粒体应激反应(mitochondrial stress response,MSR)中JmjC结构域包含蛋白3(JMJD3)-组蛋白H3第27位赖氨酸三甲基化(H3K27me3)-脑源性神经营养因子(brain derived neurotrophic factor,BDNF)轴(JMJD3-H3K27me3-BDNF轴)对MSR调控进而影响AD进程,探讨姜黄素(curcumin,CUR)通过JMJD3-H3K27me3-BDNF轴发挥对AD的保护作用,为AD的治疗提供新见解。方法:用APP/PS-1双转基因AD小鼠(n=40;n=10/组)作为观察组,野生型C57BL/6小鼠(n=10)作为对照组。观察组分别给予100mg/kg/d、200mg/kg/d、300mg/kg/d低、中、高3个剂量的CUR;采用水迷宫(MWM)测试2组小鼠认知与运动功能,用HE染色、实时定量PCR、Western blot、CCK-8法和流式细胞术评价小鼠的生物学改变。结果:AD小鼠模型表现β淀粉样蛋白(Aβ)显著积累,脑组织出现明显病理变化以及神经元凋亡水平显著上调,JMJD3、BDNF mRNA与蛋白水平下调,H3K27me3甲基化水平明显增加,MSR标志物(ClpP、HSP6、HSP-60、ATFS-1等)表达异常;JMJD3或BDNF上调可显著下调H3K27me3甲基化水平,改善MSR标志物异常和Aβ累积,提高细胞增殖水平及抑制细胞凋亡,且上调JMJD3可提升BDNF水平。结论:JMJD3可介导BDNF调控AD细胞模型Aβ与MSR;中、高剂量CUR干预可显著改善AD动物模型脑组织病理形态,可能是通过调控JMJD3-H3K27me3-BDNF轴实现抑制Aβ累积与细胞凋亡,维护MSR平衡。Objective: To analysis theregulating effect of jmjc domain in mitochondrial stress response(MSR) contains protein 3(JMJD3)-trimethylated lysine 27 on histone H3(H3K27me3)-brain derived neurotrophic factor(BDNF) axis(jmjd3-H3K27me3 BDNF axis)on MSR in the pathological mechanism of AD, And to explore the protective effect of curcumin(cur) on AD through jmjd3-H3K27me3 BDNF axis, which provides new insights for the treatment of AD. Methods: APP/PS-1 double transgenic AD mice(n = 40) and wild-type C57BL/6mice(n = 10) were used as the observation group and control group.The observation group was given CUR 100 mg/kg/d, 200 mg/kg/d and 300 mg/kg/d. All groups were tested by water maze(MWM), Hematoxylin-eosin staining(HE) staining, real-time quantitative PCR, Western blot, CCK-8 method and flow cytometry respectively. Results: It was found that AD mouse models presented a significant aggregation of Aβ,withconspicuous pathological changes in brain tissue and an increase in neuronal apoptosis. Moreover, the mRNA and protein levels of JMJD3and BDNF were down-regulated, H3K27me3 methylation levels were increased, and the MSR markers(ClpP, HSP6, HSP-60, ATFS-1) showed abnormal alterations.In in-vitro 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, as well as increased cell proliferation and inhibited apoptosis. Conclusion: JMJD3 was confirmed to regulate Aβ and MSR by mediating 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 by modulating the JMJD3-H3K27me3-BDNF axis.

关 键 词：阿尔茨海默病 姜黄素 JMJD3 H3K27me3 脑源性神经营养因子 

分 类 号：R749.1[医药卫生—神经病学与精神病学]