电针对APP/PS1小鼠学习记忆及β位淀粉样前体蛋白裂解酶1表达的影响
|
摘要
目的探讨电针治疗阿尔茨海默病的效果和作用机制。方法雄性8月龄APP/PS1小鼠24只随机分为模型组、电针组和非穴组,各8只。8只野生型小鼠为野生组。电针组电针百会、神庭,非穴组电针双侧肋下非穴区,野生组和模型组予相同抓取和固定,共28 d。干预后,Morris水迷宫测试小鼠学习记忆能力,分别采用免疫荧光和免疫组化技术检测小鼠大脑皮质β淀粉样蛋白(Aβ)和β位淀粉样前体蛋白裂解酶1 (BACE1)含量,RT-PCR检测BACE1 m RNA水平。结果与模型组比较,电针组小鼠Morris水迷宫逃避潜伏期显著下降(P <0.001),穿越平台次数显著增加(P <0.001),BACE1表达和Aβ水平显著减少(P <0.001)。结论电针百会、神庭可能通过抑制APP/PS1小鼠大脑皮质BACE1表达,降低Aβ水平,改善小鼠学习记忆能力。
Objective To explore the effects of electroacupuncture at Baihui(DU20) and Shenting(GV24) on Alzheimer's disease,and possible mechanism for it.Methods A total of 24 eight-month-old APP/PS1 male mice were randomly divided into model group(n = 8), electroacupuncture group(n = 8) and non-acupoint group(n = 8), and other eight wild-type mice were as wild-type group.The electroacupuncture group accepted electroacupuncture at Baihui and Shenting, while the non-acupoint group accepted electroacupuncture at bilateral subcostal non-acupoint area, and the wild-type group and the model group accepted the same grasping and fixing, for 28 days. Then they assessed with Morris water maze test. The levels of β-amyloid protein(Aβ) and β-site amyloid precursor protein cleaving enzyme 1(BACE1) in cerebral cortex were detected with immunohistochemistry and immunofluorescence respectively, and the level of BACE1 m RNA with RT-PCR.Results Compared with the model group, the escape latency decreased in the electroacupuncture group(P < 0.001), and the times crossing platforms increased(P < 0.001), while the expression of BACE1 and Aβ decreased(P < 0.001).Conclusion Electroacupuncture may improve the learning-memory ability by inhibiting the expression of BACE1 in the cerebral cortex of APP/PS1 mice to decreasing the level of Aβ.
Objective To explore the effects of electroacupuncture at Baihui(DU20) and Shenting(GV24) on Alzheimer's disease,and possible mechanism for it.Methods A total of 24 eight-month-old APP/PS1 male mice were randomly divided into model group(n = 8), electroacupuncture group(n = 8) and non-acupoint group(n = 8), and other eight wild-type mice were as wild-type group.The electroacupuncture group accepted electroacupuncture at Baihui and Shenting, while the non-acupoint group accepted electroacupuncture at bilateral subcostal non-acupoint area, and the wild-type group and the model group accepted the same grasping and fixing, for 28 days. Then they assessed with Morris water maze test. The levels of β-amyloid protein(Aβ) and β-site amyloid precursor protein cleaving enzyme 1(BACE1) in cerebral cortex were detected with immunohistochemistry and immunofluorescence respectively, and the level of BACE1 m RNA with RT-PCR.Results Compared with the model group, the escape latency decreased in the electroacupuncture group(P < 0.001), and the times crossing platforms increased(P < 0.001), while the expression of BACE1 and Aβ decreased(P < 0.001).Conclusion Electroacupuncture may improve the learning-memory ability by inhibiting the expression of BACE1 in the cerebral cortex of APP/PS1 mice to decreasing the level of Aβ.
引文
[1]Kumar A,Singh A,Ekavali.A review on Alzheimer's disease pathophys‐iology and its management:an update[J].Pharmacol Rep,2015,67(2)195-203.
[2]Barage S H,Sonawane K D.Amyloid cascade hypothesis:pathogenesis and therapeutic strategies in Alzheimer's disease[J].Neuropeptides2015,52(8):1-18.
[3]Mullard A.Alzheimer amyloid hypothesis lives on[J].Nature Rev Drug Discov,2016,16(1):3-5.
[4]曹江鹏,张利达,蔡兴慧,等.近5年针刺改善学习记忆临床应用与作用机制研究概况[J].辽宁中医药大学学报,2017,19(05):122-124.
[5]Perng C H,Chang Y C,Tzang R F.The treatment of cognitive dysfunc‐tion in dementia:a multiple treatments meta-analysis[J].Psychophar‐macology,2018,235(5):1571-1580.
[6]Liu W,Zhuo P,Li L,et al.Activation of brain glucose metabolism ame‐liorating cognitive impairment in APP/PS1 transgenic mice by elec‐troacupuncture[J].Free Radic Biol Med,2017,112(11):174-190.
[7]陈吉祥,吴羽楠,郑雅媗,等.电针百会穴对APP/PS1双转基因小鼠学习记忆及脑源性神经营养因子表达的影响[J].中国康复理论与实践,2015,21(6):642-647.
[8]李忠仁.实验针灸学[M].北京:中国中医药出版社,2003:325-329.
[9]Braak H,Braak E,Bohl J.Staging of Alzheimer-related cortical destruc‐tion[J].Eur Neurol,1993,33(6):403-408.
[10]Delacourte A,David J P,Sergeant N,et al.The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease[J]Neurology,1999,54(52):1158-1165.
[11]陈玉鹏,林丹红,陈立典,等.中医认知功能理论体系的构建[J].中医杂志,2016,57(1):12-15.
[12]Wang F,Zhong H,Li X,et al.Electroacupuncture attenuates reference memory impairment associated with astrocytic NDRG2 suppression in APP/PS1 transgenic mice[J].Mol Neurobiol,2014,50(2):305-313.
[13]Li G,Zhang X,Cheng H,et al.Acupuncture improves cognitive defi‐cits and increases neuron density of the hippocampus in middle-aged SAMP8 mice[J].Acupunct Med,2012,30(4):339-345.
[14]Bilkeigorzo A.Genetic mouse models of brain ageing and Alzheimer's disease[J].Pharmacol Therapeutics,2014,142(2):244-257.
[15]Lee J E,Han P L.An update of animal models of Alzheimer disease with a reevaluation of plaque depositions[J].Exp Neurobiol,2013,22(2):84-95.
[16]Garciaalloza M,Robbins E M,Zhangnunes S X,et al.Characteriza‐tion of amyloid deposition in the APPswe/PS1d E9 mouse model of Al‐zheimer disease[J].Neurobiol Dis,2006,24(3):516-524.
[17]赵凌,张富文,张虹,等.电针治疗轻度认知功能障碍:多中心随机对照研究[J].中国针灸,2012,32(9):779-784.
[18]吴羽楠,陈吉祥,陶静,等.电针百会对APP/PS1转基因小鼠学习记忆能力及Tau蛋白磷酸化的影响[J].中国康复医学杂志,2015,30(5):432-436.
[19]Bodendorf U,Danner S,Fischer F,et al.Expression of human betasecretase in the mouse brain increases the steady-state level of beta-am‐yloid[J].J Neurochem,2010,80(5):799-806.
[20]Sathya M,Premkumar P,Karthick C,et al.BACE1 in Alzheimer's dis‐ease[J].Clinica Chimica Acta,2012,414(4546):171-178.
[21]Vassar R.BACE1 inhibitor drugs in clinical trials for Alzheimer's dis‐ease[J].Alzheimers Res Ther,2014,6(9):89-103.
[22]Yan R.Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs[J].Transl Neurodegener,2016,5(1):13-24.
[23]Dong W G,Wang F,Chen Y,et al.Electroacupuncture reduces Aβpro‐duction and BACE1 expression in SAMP8 mice[J].Front Aging Neu‐rosci,2015,7(7):148-155.
[24]Lan Z,Cong S,Jin C,et al.Icariin decreases the expression of APPand BACE-1 and reduces theβ-amyloid burden in an APP transgenic mouse model of Alzheimer's disease[J].Int J Biol Sci,2014,10(2):181-191.
[25]Tamayev R,Matsuda S,Arancio O,et al.β-but notγ-secretase proteol‐ysis of APP causes synaptic and memory deficits in a mouse model of dementia[J].EMBO Mol Med,2012,4(3):171-179.
[26]Kim S,Sato Y,Mohan P S,et al.Evidence that the RAB5 effector AP‐PL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease[J].Mol Psychiatry,2016,21(5):707-716.
[27]Lauritzen I,Pardossi-Piquard R,Bourgeois A,et al.Intraneuronal ag‐gregation of theβ-CTF fragment of APP(C99)induces Aβ-independent lysosomal-autophagic pathology[J].Acta Neuropathol,2016,132(2):257-276.
[2]Barage S H,Sonawane K D.Amyloid cascade hypothesis:pathogenesis and therapeutic strategies in Alzheimer's disease[J].Neuropeptides2015,52(8):1-18.
[3]Mullard A.Alzheimer amyloid hypothesis lives on[J].Nature Rev Drug Discov,2016,16(1):3-5.
[4]曹江鹏,张利达,蔡兴慧,等.近5年针刺改善学习记忆临床应用与作用机制研究概况[J].辽宁中医药大学学报,2017,19(05):122-124.
[5]Perng C H,Chang Y C,Tzang R F.The treatment of cognitive dysfunc‐tion in dementia:a multiple treatments meta-analysis[J].Psychophar‐macology,2018,235(5):1571-1580.
[6]Liu W,Zhuo P,Li L,et al.Activation of brain glucose metabolism ame‐liorating cognitive impairment in APP/PS1 transgenic mice by elec‐troacupuncture[J].Free Radic Biol Med,2017,112(11):174-190.
[7]陈吉祥,吴羽楠,郑雅媗,等.电针百会穴对APP/PS1双转基因小鼠学习记忆及脑源性神经营养因子表达的影响[J].中国康复理论与实践,2015,21(6):642-647.
[8]李忠仁.实验针灸学[M].北京:中国中医药出版社,2003:325-329.
[9]Braak H,Braak E,Bohl J.Staging of Alzheimer-related cortical destruc‐tion[J].Eur Neurol,1993,33(6):403-408.
[10]Delacourte A,David J P,Sergeant N,et al.The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease[J]Neurology,1999,54(52):1158-1165.
[11]陈玉鹏,林丹红,陈立典,等.中医认知功能理论体系的构建[J].中医杂志,2016,57(1):12-15.
[12]Wang F,Zhong H,Li X,et al.Electroacupuncture attenuates reference memory impairment associated with astrocytic NDRG2 suppression in APP/PS1 transgenic mice[J].Mol Neurobiol,2014,50(2):305-313.
[13]Li G,Zhang X,Cheng H,et al.Acupuncture improves cognitive defi‐cits and increases neuron density of the hippocampus in middle-aged SAMP8 mice[J].Acupunct Med,2012,30(4):339-345.
[14]Bilkeigorzo A.Genetic mouse models of brain ageing and Alzheimer's disease[J].Pharmacol Therapeutics,2014,142(2):244-257.
[15]Lee J E,Han P L.An update of animal models of Alzheimer disease with a reevaluation of plaque depositions[J].Exp Neurobiol,2013,22(2):84-95.
[16]Garciaalloza M,Robbins E M,Zhangnunes S X,et al.Characteriza‐tion of amyloid deposition in the APPswe/PS1d E9 mouse model of Al‐zheimer disease[J].Neurobiol Dis,2006,24(3):516-524.
[17]赵凌,张富文,张虹,等.电针治疗轻度认知功能障碍:多中心随机对照研究[J].中国针灸,2012,32(9):779-784.
[18]吴羽楠,陈吉祥,陶静,等.电针百会对APP/PS1转基因小鼠学习记忆能力及Tau蛋白磷酸化的影响[J].中国康复医学杂志,2015,30(5):432-436.
[19]Bodendorf U,Danner S,Fischer F,et al.Expression of human betasecretase in the mouse brain increases the steady-state level of beta-am‐yloid[J].J Neurochem,2010,80(5):799-806.
[20]Sathya M,Premkumar P,Karthick C,et al.BACE1 in Alzheimer's dis‐ease[J].Clinica Chimica Acta,2012,414(4546):171-178.
[21]Vassar R.BACE1 inhibitor drugs in clinical trials for Alzheimer's dis‐ease[J].Alzheimers Res Ther,2014,6(9):89-103.
[22]Yan R.Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs[J].Transl Neurodegener,2016,5(1):13-24.
[23]Dong W G,Wang F,Chen Y,et al.Electroacupuncture reduces Aβpro‐duction and BACE1 expression in SAMP8 mice[J].Front Aging Neu‐rosci,2015,7(7):148-155.
[24]Lan Z,Cong S,Jin C,et al.Icariin decreases the expression of APPand BACE-1 and reduces theβ-amyloid burden in an APP transgenic mouse model of Alzheimer's disease[J].Int J Biol Sci,2014,10(2):181-191.
[25]Tamayev R,Matsuda S,Arancio O,et al.β-but notγ-secretase proteol‐ysis of APP causes synaptic and memory deficits in a mouse model of dementia[J].EMBO Mol Med,2012,4(3):171-179.
[26]Kim S,Sato Y,Mohan P S,et al.Evidence that the RAB5 effector AP‐PL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease[J].Mol Psychiatry,2016,21(5):707-716.
[27]Lauritzen I,Pardossi-Piquard R,Bourgeois A,et al.Intraneuronal ag‐gregation of theβ-CTF fragment of APP(C99)induces Aβ-independent lysosomal-autophagic pathology[J].Acta Neuropathol,2016,132(2):257-276.