CD147对阿尔茨海默病模型大鼠学习记忆能力的干预作用
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摘要
目的探讨细胞外基质金属蛋白酶诱导因子(CD147)对阿尔茨海默病模型大鼠学习记忆能力的干预作用。方法健康Sprague-Dawley大鼠按随机数字表法分为假手术组、模型组和CD147组,每组20只。所有大鼠10%水合氯醛(0.3 g/kg)腹腔注射麻醉,模型组和CD147组大鼠于双侧海马CA1区注入10μg的Aβ1~40,假手术组大鼠于同一部位注射等量的生理盐水。术后48 h,CD147组大鼠于双侧脑室注射CD147 c DNA,模型组和假手术组大鼠于同一部位注射等量生理盐水。采用Morris水迷宫实验对各组大鼠的学习记忆能力进行测试。采用蛋白印迹法检测β-淀粉样蛋白(Aβ)和γ-分泌酶表达。结果从第3天开始,模型组大鼠逃避潜伏期时间较假手术组延长,而CD147组较模型组减少,差异均有统计学意义(P<0.05)。模型组大鼠经过平台次数和经平台停留时间较假手术组减少,而CD147组较模型组均增加,差异有统计学意义(P<0.05)。模型组大鼠脑组织Aβ和γ-分泌酶表达较假手术组增加,而CD147组较模型组大鼠减少,差异有统计学意义(P<0.05)。结论外源性CD147能够显著改善AD模型大鼠学习记忆能力,其具体机制可能与调节γ-分泌酶活性和下调Aβ的表达有关。
Objective To investigate the intervention effect of CD147 on learning and memory ability in rat model ofAlzheimer's disease.MethodsA total of 60 healthy Sprague-Dawley rats were randomly divided into sham operationgroup, model group and CD147 group, 20 rats in each group. All of the rats were anesthetized with intraperitoneal injection of10% chloral hydrate(0.3 g/kg). The rats in the model group and the CD147 group were injected with Aβ1-40(10 μg) in thebilateral hippocampal CA1 regions, while the rats in the sham operation group were injected with the same amount of salineat the same sites. After 48 h, the rats in CD147 group were injected with CD147 c DNA in the bilateral ventricles, while therats in model group and sham operation group were injected the same amount of saline at the same sites. Morris water mazetest was used to detect the ability of learning and memory of rats. The expressions of β amyloid protein(Aβ) and γ-secretasewere detected by Western blot assay.ResultsThe escape latency was significantly longer in model group than that of shamoperation group, while which was significantly lower in CD147 group than that of model group(P<0.05). The number oftimes across the platform and the time of staying on platform were significantly lower in model group than those of shamoperation group, while which was significantly higher in the CD147 group than that of model group(P<0.05). Theexpressions of Aβ and γ-secretase were increased significantly in model group compared to those of sham operation group,while which were significantly decreased in CD147 group compared with those of model group(P<0.05).Conclusion Exogenous CD147 can significantly improve the learning and memory ability of AD rats, and its specific mechanism may berelated to regulating the activity of γ-secretase and down regulating the expression of Aβ.
Objective To investigate the intervention effect of CD147 on learning and memory ability in rat model ofAlzheimer's disease.MethodsA total of 60 healthy Sprague-Dawley rats were randomly divided into sham operationgroup, model group and CD147 group, 20 rats in each group. All of the rats were anesthetized with intraperitoneal injection of10% chloral hydrate(0.3 g/kg). The rats in the model group and the CD147 group were injected with Aβ1-40(10 μg) in thebilateral hippocampal CA1 regions, while the rats in the sham operation group were injected with the same amount of salineat the same sites. After 48 h, the rats in CD147 group were injected with CD147 c DNA in the bilateral ventricles, while therats in model group and sham operation group were injected the same amount of saline at the same sites. Morris water mazetest was used to detect the ability of learning and memory of rats. The expressions of β amyloid protein(Aβ) and γ-secretasewere detected by Western blot assay.ResultsThe escape latency was significantly longer in model group than that of shamoperation group, while which was significantly lower in CD147 group than that of model group(P<0.05). The number oftimes across the platform and the time of staying on platform were significantly lower in model group than those of shamoperation group, while which was significantly higher in the CD147 group than that of model group(P<0.05). Theexpressions of Aβ and γ-secretase were increased significantly in model group compared to those of sham operation group,while which were significantly decreased in CD147 group compared with those of model group(P<0.05).Conclusion Exogenous CD147 can significantly improve the learning and memory ability of AD rats, and its specific mechanism may berelated to regulating the activity of γ-secretase and down regulating the expression of Aβ.
引文
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[7]Liu X,Zuo H,Wang D,et al.Improvement of spatial memorydisorder and hippocampal damage by exposure to electromagneticfields in an Alzheimer’s disease rat model[J].PLo S One,2015,10(5):e0126963.doi:10.1371/journal.pone.0126963.
[8]张琳琳,宋宛珊,王凯,等.阿尔茨海默病发病机制及药物治疗研究进展[J].世界中医药,2017,12(5):1200-1203.Zhang LL,Song WS,Wang K,et al.Progress in mechanism of pathogenesisand medical treatment of Alzheimer’s disease[J].World ChinMed,2017,12(5):1200-1203.doi:10.3969/j.issn.1673-7202.2017.05.058.
[9]徐金静,方力群,赵春慧,等.β淀粉样蛋白对阿尔茨海默病转基因果蝇认知功能的影响[J].国际神经病学神经外科杂志,2013,30(2):101-104.Xu JJ,Fang LQ,Zhao CH,et al.Effect ofβ-amyloid proteins on cognitive functions in transgenic drosophilawith Alzheimer’s disease[J].J Int Neurol Neurosurg,2013,30(2):101-104.
[10]Aruoma OI,Jen SS,Watts HR,et al.Acute and chronic effects ofintravitreally injected beta-amyloid on the neurotransmitter systemin the retina[J].Toxicology,2009,256(1/2):92-100.doi:10.1016/j.tox.2008.11.007.
[11]谭展望,胡海燕,陈翔,等.清心开窍方皂苷对AD大鼠大脑皮层及海马区Bax、Bcl-2、Aβ及βAPP表达的影响[J].中国中西医结合杂志,2012,32(9):1258-1263.Tan ZW,Hu HY,Chen X,et al.Effect of Qingxin Kaiqiao Recipe Saponin on the expressionsof Bax,Bcl-2,Aβ,andβAPP in the cortex and hippocampus ofAlzheimer’s disease rats[J].CJITWM,2012,32(9):1258-1263.
[12]Arora K,Alfulaij N,Higa JK,et al.Impact of sustained exposure toβ-amyloid on calcium homeostasis and neuronal integrity in modelnerve cell system expressingα4β2 nicotinic acetylcholine receptors[J].J Biol Chem,2013,288(16):11175-11190.doi:10.1074/jbc.M113.453746.
[13]邓青山,马全红,徐如祥.人β-分泌酶与阿尔茨海默病[J].中华神经创伤外科电子杂志,2015,1(4):45-48.Deng QS,Ma QH,Xu RX.Human beta-secretase and Alzheimer’s disease[J].Chin JNeurotrauma Surg(Electronic Edition),2015,1(4):45-48.doi:10.3877/cma.j.issn.2095-9141.2015.04.011.
[14]Zhou S,Zhou H,Walian PJ,et al.CD147 is a regulatory subunit oftheγ-secretase complex in Alzheimer’s disease amyloidβ-peptideproduction[J].Proc Natl Acad Sci,2005,102(21):7499-7504.doi:10.1073/pnas.0502768102.
[15]张锦巍,井丽娟,孙亚平,等.CD147超表达对γ-分泌酶影响的临床研究[J].重庆医学,2012,41(36):3801-3806.Zhang JW,Jing LJ,Sun YP,et al.Effect of over expressed CD147 onγ-secretase[J].Chongqing Med,2012,42(36):3801-3806.doi:10.3969/j.issn.1671-8348.2012.36.001.
[16]智孔亮,辛娜,曹志红,等.细胞外基质金属蛋白酶诱导因子与阿尔茨海默病γ-分泌酶的相关性研究[J].国际神经病学神经外科学杂志,2015,42(3):244-247.Zhi KL,Xin N,Cao ZH,et al.Relationship between extracellular matrix metalloproteinaseinducer andγ-secretase in Alzheimer’s disease[J].J Int NeurolNeurosurg,2015,42(3):244-247.doi:10.16636/j.cnki.jinn.2015.03.024.
[2]何颖,王超,王德才.阿尔茨海默病的非治疗药物及新靶点研究进展[J].中国医药导报,2014,11(6):162-166.He Y,Wang C,Wang DC.Research progress for non-treatment drug and newtargets in Alzheimer disease[J].Chin Med Herald,2014,11(6):162-166.
[3]胡海燕.β-淀粉样蛋白在阿尔茨海默病中的作用及中药多靶点对抗研究进展[J].中华中医药学刊,2012,30(3):488-492.Hu HY.Against research progress of beta amyloid protein in therole of Alzheimer disease and traditional Chinese medicine therapy by multiple targets[J].Chin Arch Tradit Chin Med,2012,30(3):488-492.
[4]Roher AE,Maarouf CL,Kokjohn TA,et al.Neuropathological andbiochemical assessments of an Alzheimer’s disease patient treatedwith theγ-secretase inhibitor semagacestat[J].Am JNeurodegener Dis,2014,3(3):115-133.
[5]Nahalkova J,Volkmann I,Aoki M,et al.CD147,aγ-secretaseassociated protein is upregulated in Alzheimer’s disease brain andits cellular trafficking is affected by presenilin-2[J].NeurochemInt,2010,56(1):67-76.doi:10.1016/j.neuint.2009.09.003.
[6]智孔亮,辛娜,曹志红,等.细胞外基质金属蛋白酶诱导因子与阿尔茨海默病β-淀粉样蛋白的相关性研究[J].临床和实验医学杂志,2016,15(4):342-345.Zhi KL,Xin N,Cao ZH,et al.Therelationship between CD147 andβ-amyloid protein of Alzheimer’sdisease[J].J Clin Exp Med,2016,15(4):342-345.doi:10.3969/j.issn.1671-4695.2016.04.014.
[7]Liu X,Zuo H,Wang D,et al.Improvement of spatial memorydisorder and hippocampal damage by exposure to electromagneticfields in an Alzheimer’s disease rat model[J].PLo S One,2015,10(5):e0126963.doi:10.1371/journal.pone.0126963.
[8]张琳琳,宋宛珊,王凯,等.阿尔茨海默病发病机制及药物治疗研究进展[J].世界中医药,2017,12(5):1200-1203.Zhang LL,Song WS,Wang K,et al.Progress in mechanism of pathogenesisand medical treatment of Alzheimer’s disease[J].World ChinMed,2017,12(5):1200-1203.doi:10.3969/j.issn.1673-7202.2017.05.058.
[9]徐金静,方力群,赵春慧,等.β淀粉样蛋白对阿尔茨海默病转基因果蝇认知功能的影响[J].国际神经病学神经外科杂志,2013,30(2):101-104.Xu JJ,Fang LQ,Zhao CH,et al.Effect ofβ-amyloid proteins on cognitive functions in transgenic drosophilawith Alzheimer’s disease[J].J Int Neurol Neurosurg,2013,30(2):101-104.
[10]Aruoma OI,Jen SS,Watts HR,et al.Acute and chronic effects ofintravitreally injected beta-amyloid on the neurotransmitter systemin the retina[J].Toxicology,2009,256(1/2):92-100.doi:10.1016/j.tox.2008.11.007.
[11]谭展望,胡海燕,陈翔,等.清心开窍方皂苷对AD大鼠大脑皮层及海马区Bax、Bcl-2、Aβ及βAPP表达的影响[J].中国中西医结合杂志,2012,32(9):1258-1263.Tan ZW,Hu HY,Chen X,et al.Effect of Qingxin Kaiqiao Recipe Saponin on the expressionsof Bax,Bcl-2,Aβ,andβAPP in the cortex and hippocampus ofAlzheimer’s disease rats[J].CJITWM,2012,32(9):1258-1263.
[12]Arora K,Alfulaij N,Higa JK,et al.Impact of sustained exposure toβ-amyloid on calcium homeostasis and neuronal integrity in modelnerve cell system expressingα4β2 nicotinic acetylcholine receptors[J].J Biol Chem,2013,288(16):11175-11190.doi:10.1074/jbc.M113.453746.
[13]邓青山,马全红,徐如祥.人β-分泌酶与阿尔茨海默病[J].中华神经创伤外科电子杂志,2015,1(4):45-48.Deng QS,Ma QH,Xu RX.Human beta-secretase and Alzheimer’s disease[J].Chin JNeurotrauma Surg(Electronic Edition),2015,1(4):45-48.doi:10.3877/cma.j.issn.2095-9141.2015.04.011.
[14]Zhou S,Zhou H,Walian PJ,et al.CD147 is a regulatory subunit oftheγ-secretase complex in Alzheimer’s disease amyloidβ-peptideproduction[J].Proc Natl Acad Sci,2005,102(21):7499-7504.doi:10.1073/pnas.0502768102.
[15]张锦巍,井丽娟,孙亚平,等.CD147超表达对γ-分泌酶影响的临床研究[J].重庆医学,2012,41(36):3801-3806.Zhang JW,Jing LJ,Sun YP,et al.Effect of over expressed CD147 onγ-secretase[J].Chongqing Med,2012,42(36):3801-3806.doi:10.3969/j.issn.1671-8348.2012.36.001.
[16]智孔亮,辛娜,曹志红,等.细胞外基质金属蛋白酶诱导因子与阿尔茨海默病γ-分泌酶的相关性研究[J].国际神经病学神经外科学杂志,2015,42(3):244-247.Zhi KL,Xin N,Cao ZH,et al.Relationship between extracellular matrix metalloproteinaseinducer andγ-secretase in Alzheimer’s disease[J].J Int NeurolNeurosurg,2015,42(3):244-247.doi:10.16636/j.cnki.jinn.2015.03.024.