基于内质网应激PERK-ATF4-CHOP信号通路探讨白藜芦醇对AD大鼠脑神经细胞凋亡的影响  

Effect of resveratrol on apoptosis of cerebral nerve cells in AD rats based on endoplasmic reticulum stress PERK-ATF4-CHOP signaling pathway

作　　者：李彪[1] 台勇 迟正锁 许超 LI Biao;TAI Yong;CHI Zheng-Suo;XU Chao(Department of Psychiatry,Wuhan Mental Health Center,Wuhan 430030,China)

机构地区：[1]武汉市精神卫生中心精神科,武汉430030 [2]温州康宁医院精神科,温州325007 [3]蚌埠海豚脑康医院二病区精神科,蚌埠233000

出　　处：《中国免疫学杂志》2020年第20期2443-2446,2450,共5页Chinese Journal of Immunology

基　　金：湖北省卫生和计划生育联合基金青年人才项目(WJ2018H0159)。

摘　　要：目的:探讨白藜芦醇(RESV)基于内质网应激蛋白激酶R样内质网激酶(PERK)-转录活化因子4(ATF4)-C/EBP同源蛋白(CHOP)信号通路对阿尔茨海默病(AD)大鼠脑神经细胞凋亡的影响。方法:健康大鼠海马区注射β淀粉样蛋白(Aβ1~40)建立AD模型,随机分为AD模型组、RESV低剂量组、RESV中剂量组、RESV高剂量组,RESV低、中、高剂量组大鼠分别腹腔注射10、20、40 mg/kg RESV,另设假手术组,每组10只,观察各组大鼠脑组织免疫组化情况、TUNEL染色情况、Caspase-3、GPR78、PERK、ATF4、CHOP蛋白表达水平。结果:假手术组大鼠海马神经细胞基本无Aβ1~40阳性表达,与假手术组相比,AD模型组大鼠海马神经细胞Aβ1~40阳性表达细胞显著增多(P<0.05),凋亡率显著升高(P<0.05),大鼠脑组织中Caspase-3、GPR78、PERK、ATF4、CHOP蛋白表达水平显著升高(P<0.05);与AD模型组相比,RESV低、中、高剂量组大鼠海马神经细胞Aβ1~40阳性表达细胞显著减少(P<0.05),凋亡率显著减少(P<0.05),Caspase-3、GPR78、PERK、ATF4、CHOP蛋白表达水平不同程度降低(P<0.05)。结论:RESV可显著减少AD大鼠脑神经细胞Aβ1~40沉积,抑制海马神经细胞凋亡,调节凋亡关键蛋白Caspase-3表达,可能通过参与PERK-ATF4-CHOP信号通路介导的细胞凋亡抑制内质网应激,发挥脑神经细胞保护作用。Objective:To explore effect of resveratrol(RESV)on apoptosis of cerebral nerve cells in rats with Alzheimer′s disease(AD)based on endoplasmic reticulum stress signaling pathway of PKR-like ER kinase(PERK)-activating transcription factor 4(ATF4)-C/EBP-homologous protein(CHOP).Methods:AD model was established by injecting amyloidβ(Aβ1~40)into fhippo-campus of healthy rats and divided into AD model group,RESV low-dose group,RESV medium-dose group and RESV high-dose group.RESV low-dose,medium-dose and high-dose groups were intraperitoneally injected with RESV at doses of 10,20 and 40 mg/kg,another sham operation group was established,with 10 rats in each group.Immunohistochemistry,TUNEL staining and protein expression levels of Caspase-3,GPR78,PERK,ATF4 and CHOP in cerebral tissue were observed in each group.Results:There was no positive expression of Aβ1~40 in hippocampal neurons in sham operation group.Compared with sham operation group,Aβ1~40 positive cells in hippocampal neurons were increased significantly in AD model group(P<0.05),and apoptosis rate was significantly increased(P<0.05),and protein expression levels of Caspase-3,GPR78,PERK,ATF4 and CHOP in cerebral tissue were significantly increased(P<0.05).Compared with AD model group,Aβ1~40 positive cells in hippocampal neurons in RESV low-dose,medium-dose and high-dose groups were significantly decreased(P<0.05),and apoptosis rate was significantly decreased(P<0.05),and protein expression levels of Caspase-3,GPR78,PERK,ATF4 and CHOP were decreased to different degrees(P<0.05).Conclusion:RESV can significantly reduce deposition of Aβ1~40 in cerebral nerve cells of AD rats,inhibit apoptosis of hippocampal neurons and regulate expression of Caspase-3,which may play a role in protecting cerebral nerve cells by involving in apoptosis of PERK-ATF4-CHOP signaling pathway and inhibiting endoplasmic reticulum stress.

关 键 词：内质网应激 PERK-ATF4-CHOP 白藜芦醇 AD大鼠 脑神经 凋亡 

分 类 号：R963[医药卫生—微生物与生化药学]