电针对阿尔茨海默病大鼠学习记忆能力及前额叶P35/P25-周期蛋白依赖性激酶5-Tau蛋白磷酸化通路的影响

doi:10.3969/j.issn.1006-9771.2020.00.006

Abstract

Abstract:

Objective To observe the effect of electroacupuncture at Baihui (DU20) and Shenshu (BL23) acupoints on learning-memory ability and expression of the relative protein of P35/P25-cyclin-dependent kinase 5 (CDK5)-Tau phosphorylation signaling pathway in the prefrontal cortex (PFC) in rats with Alzheimer's disease (AD), so as to reveal its potential mechanisms in treating AD. Methods Male adult Sprague-Dawley rats were randomly divided into normal control group, sham group, model group and treatment group with six rats in each group. The AD model was constructed by bilateral hippocampal injection of Aβ_25-35 in latter two groups. Equal amount of normal saline was injected into the sham group. The treatment group was acupunctured at Baihui and Shenshu once a day for ten days. All the rats were tested with Morris Water Maze. Immunohistochemistry staining and Western blotting were used to detect the related protein of P35/P25-CDK5-Tau protein phosphorylation in the PFC.Results Compared with the normal control group and the sham group, the escape latency and escape length increased (P< 0.05) and the times crossing the platform reduced (P< 0.05) in the model group; compared with the model group, the escape latency and escape length reduced (P< 0.05), and the times crossing the platform increased (P< 0.05) in the treatment group. The optical density of P35/P25 and CDK5 were significantly higher in the model group than in the normal control group and the sham group (P< 0.01), and they were lower in the treatment group than in the model group (P< 0.001). The relative expression of P35/P25, CDK5, Tau[pS199] and Tau[pS202] were higher in the model group than in the normal control group and the sham group (P< 0.05), and the expression of the above proteins was lower in the treatment group than in the model group (P< 0.05).Conclusion Electroacupuncture could improve the learning-memory and spatial exploration ability, which associate with inhabiting the P35/P25-CDK5-Tau protein phosphorylation signaling pathway in the PFC to delay the development of AD.

Key words: Alzheimer's disease, electroacupuncture, prefrontal cortex, P35/P25-cyclin-dependent kinase 5-Tau phosphorylation, rats

CLC Number:

R749.1

WANG Yi-ying,TANG Cheng-lin,QIU Guo-ping,XU Jin,LONG Ling,XU Yi,WANG Jian-rong,GAN Sheng-wei,SHENG Hua-jun,ZHU Shu-juan. Effects of Electroacupuncture on Learning-memory and P35/P25-Cyclin-dependent Kinase 5-Tau Phosphorylation Signal Pathway in Prefrontal Cortex of Rats with Alzheimer's Disease[J]. 《Chinese Journal of Rehabilitation Theory and Practice》, 2020, 26(6): 654-661.

Figures/Tables 8

References 32

[1]	Habtemariam S. Natural products in Alzheimer's disease therapy: would old therapeutic approaches fix the broken promise of modern medicines?[J]. Molecules, 2019, 24(8):1519. doi: 10.3390/molecules24081519
[2]	Sigurdsson T, Duvarci S. Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease[J]. Front Syst Neurosci, 2016, 9:190.
[3]	Pfeffer A, Munder T, Schreyer S, et al. Behavioral and psychological symptoms of dementia (BPSD) and impaired cognition reflect unsuccessful neuronal compensation in the pre-plaque stage and serveas early markers for Alzheimer’s disease in the APP23 mouse model[J]. Behav Brain Res, 2018, 347(3):300-313. doi: 10.1016/j.bbr.2018.03.030
[4]	Huey E D, Lee S, Cheran G, et al. Alzheimer’s disease neuroimaging initiative. Brain regions involved in arousal and reward processing are associated with apathy in Alzheimer's disease and frontotemporal dementia[J]. Alzheimers Dis, 2017, 55(2):551-558.
[5]	Carlén M. What constitutes the prefrontal cortex?[J]. Science, 2017, 358(6362):478-482. doi: 10.1126/science.aan8868
[6]	杨清华, 郭玲, 陈清, 等. “益肾调督”电针法对阿尔茨海默病小鼠大脑海马老年斑形成的影响[J]. 针刺研究, 2018, 43(4):215-220.
[7]	李芙, 李丽娜, 王鑫, 等. 电针“百会”“涌泉”对APP/PS 1双转基因小鼠海马β淀粉样蛋白及低密度脂蛋白受体相关蛋白-1水平的影响[J]. 针刺研究, 2015, 40(1):30-34, 55.
[8]	杨清华, 郭玲, 陈清, 等. 电针刺激对APP/PS1双转基因阿尔兹海默病模型小鼠皮质老年斑形成的影响及机制研究[J]. 中国康复医学杂志, 2018, 33(7):770-776.
[9]	Hashiguchi M, Saito T, Hisanaga S, et al. Truncation of CDK5 activator P35 induces intensive phosphorylation of Ser202/Thr205 of human tau[J]. J Biol Chem, 2002, 277(46):44525-44530. pmid: 12226093
[10]	Lee M S, Kwon Y T, Li M, et al. Neurotoxicity induces cleavage of P35 to P25 by calpain[J]. Nature, 2000, 405(678):360-364. doi: 10.1038/35012636
[11]	Patrick G N, Zukerberg L, Nikolic M, et al. Conversion of P35 to P25 deregulates CDK5 activity and promotes neurodegeneration[J]. Nature, 1999, 402(6762):615-622. pmid: 10604467
[12]	谭昭君, 况利, 艾明, 等. 自杀未遂抑郁症患者海马在静息态下功能连接的改变[J]. 重庆医科大学学报, 2018, 43(8):1076-1082.
[13]	Phillips M L, Drevets W C, Rauch S L, et al. Neurobiology of emotionperception II: implications formajor psychiatric disorders[J]. Biol Psychiatry, 2003, 54(5):515-528. doi: 10.1016/S0006-3223(03)00171-9
[14]	Fitzgerald P B, Laird A R, Maller J, et al. A meta-analytic study of changes in brain activation indepression[J]. Hum Brain Mapp, 2008, 29(6):683-695. pmid: 17598168
[15]	Matsumoto A, Kakigi R. Subliminal semantic priming changes the dynamic causal influence between the left frontal and temporal cortex[J]. J Cogn Neurosci, 2014, 26(1):165-174. doi: 10.1162/jocn_a_00472
[16]	李传明, 王健, 桂莉, 等. AD和MCI病人前额叶注意功能区fMRI检测[J]. 青岛大学医学院学报, 2009, 45(4):331-334.
[17]	王旭, 张小强, 刘静, 等. 原花青素对Aβ_(25-35)介导的tau蛋白过度磷酸化及P38 MAPK信号通路的影响[J]. 癌变·畸变·突变, 2019, 31(2):96-101, 110.
[18]	Mohamed T, Gujral S S, Rao P P N. Tau derived hexapeptide AcPHF6 promotes beta-amyloid (Aβ) fibrillogenesis[J]. ACS Chem Neurosci, 2018, 9(4):773-782. doi: 10.1021/acschemneuro.7b00433 pmid: 29239599
[19]	Angelo M, Plattner F, Giese K P. Cyclin-dependent kinase 5 in synaptic plasticity, learning and memory[J]. J Neurochem, 2006, 99(2):353-370. pmid: 17029592
[20]	Dhavan R, Tsai L H. A decade of CDK5[J]. Nat Rev Mol Cell Biol, 2001, 2(10):749-759. doi: 10.1038/35096019
[21]	黄天文, 陈晓春, 张静, 等. 钙蛋白酶-细胞周期依赖性蛋白激酶5通路参与β淀粉样蛋白25-35诱导的tau蛋白过度磷酸化[J]. 中华神经科杂志, 2006, 39(7):477-480.
[22]	丁绍红, 施建华, 尹晓敏, 等. PKA、GSK-3β和CDK5对微管相关蛋白tau的位点特异性磷酸化[J]. 南通大学学报(医学版), 2006, 26(4):235-238.
[23]	Shi L L, Yang W N, Chen X L, et al. The protective effects of tanshinone IIA on neurotoxicity induced by β-amyloid protein through calpain and the P35/CDK5 pathway in primary corticalneurons[J]. NeurochemInt, 2012, 61(2):227-235.
[24]	Tandon A, Yu H, Wang L, et al. Brain levels of CDK5 activator P25 are not increased in Alzheimer's or other neurodegenerativediseases with neurofibrillary tangles[J]. J Neurochem, 2003, 86(3):572-581. doi: 10.1046/j.1471-4159.2003.01865.x
[25]	Engmann O, Hortobágyi T, Thompson A J, et al. Cyclin-dependent kinase 5 activator P25 isgenerated during memory formation and is reduced at an early stage in Alzheimer's disease[J]. Biol Psychiatry, 2011, 70(2):159-168. doi: 10.1016/j.biopsych.2011.04.011
[26]	王悦, 张文婷, 张丽娜, 等. Alzheimer病治疗新靶点CDK5及其抑制剂的研究进展[J]. 中国药物化学杂志, 2009, 19(1):71-77.
[27]	李雅悦, 李广诚, 朱宏, 等. 针刺对阿尔茨海默病模型小鼠行为学及线粒体分裂蛋白1、融合蛋白1表达和超微结构的影响[J]. 中国中医药信息杂志, 2018, 25(2):59-64.
[28]	王颖, 李威, 张亢亢, 等. 不同频率电针对阿尔茨海默病大鼠学习记忆能力和海马突触的影响[J]. 中国康复理论与实践, 2016, 22(6):635-639.
[29]	李虹霖, 孙琦月, 高伟, 等. 针康法对APP/PS1小鼠海马神经细胞凋亡的影响[J]. 吉林中医药, 2019, 39(12):1631-1634.
[30]	豁银成, 孙国杰, 杜艳军. 针灸预刺激对AD大鼠神经元凋亡相关蛋白Bcl-2、NF-κB的影响[J]. 湖北中医学院学报, 2010, 12(3):16-18.
[31]	王少锦, 康锁彬, 李爱英. 针刺拟痴呆大鼠对脑内自由基系统与胆碱能系统功能影响相关性的分析[J]. 针刺研究, 2004, 29(2):102-106.
[32]	姜美驰, 梁静, 张玉杰, 等. 针刺“四关”穴对阿尔茨海默病大鼠学习记忆及海马区β淀粉样蛋白42、白介素-1β和白介素-2的影响[J]. 针刺研究, 2016, 41(2):113-118.

组别	n	逃避潜伏期(s)	搜索路径(cm)
正常对照组	6	31.38±4.086	783.3±110.40
假手术组	6	37.30±2.591	815.3±67.10
模型组	6	36.78±4.032	890.7±101.20
电针组	6	33.14±3.898	719.4±66.82
F值		0.597	0.647
P值		0.624	0.593

组别	n	第3天	第4天	第5天	第6天
正常对照组	6	19.29±1.652	17.59±1.064	12.98±2.355	9.34±0.980
假手术组	6	23.14±2.211	18.22±2.162	13.24±2.199	11.64±2.117
模型组	6	35.71±2.896^a,b	33.80±2.056^a,b	30.43±3.222^a,b	24.79±3.192^a,b
电针组	6	19.67±3.316^c	19.17±2.320^c	13.49±1.505^c	12.64±2.991^c
F值	6	8.787	15.36	12.85	13.64
P值	6	0.001	< 0.001	< 0.001	< 0.001

组别	n	第3天	第4天	第5天	第6天
正常对照组	6	359.9±57.27	296.2±20.04	218.4±33.42	137.2±15.05
假手术组	6	392.0±38.6	335.5±30.55	219.8±30.86	202.3±32.48
模型组	6	683.3±106.2^a,b	587.6±39.98^a,b	481.4±62.57^a,b	370.8±47.82^a,b
电针组	6	353.9±65.62^c	304.3±61.18^c	248.6±27.25^c	160.2±25.24^c
F值	6	4.919	11.550	9.591	10.610
P值	6	0.013	< 0.001	< 0.001	< 0.001

组别	n	穿越平台次数
正常对照组	6	3.917±0.6994
假手术组	6	3.083±0.5128
模型组	6	1.917±0.4876^a,b
电针组	6	3.167±0.4641^c
F值		4.371
P值		0.009

组别	n	P35/P25	CDK5	Tau5
正常对照组	6	0.255±0.006	0.265±0.011	0.267±0.013
假手术组	6	0.271±0.009	0.269±0.009	0.245±0.006
模型组	6	0.346±0.017^a,b	0.369±0.016^a,b	0.274±0.012
电针组	6	0.255±0.008^c	0.270±0.006^c	0.276±0.007
F值		16.740	19.790	2.183
P值		< 0.001	< 0.001	0.122

Effects of Electroacupuncture on Learning-memory and P35/P25-Cyclin-dependent Kinase 5-Tau Phosphorylation Signal Pathway in Prefrontal Cortex of Rats with Alzheimer's Disease

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组别	n	Tau5	Tau[pS199]	Tau[pS202]	CDK5	P35	P25
正常对照组	6	2.231±0.186	1.064±0.073	0.880±0.096	0.707±0.176	0.672±0.077	0.544±0.088
假手术组	6	2.351±0.173	1.217±0.068	1.218±0.067	0.882±0.126	0.8204±0.056	0.616±0.135
模型组	6	2.322±0.202	1.591±0.144^a,b	1.876±0.139^d,e	1.340±0.118^g,h	1.200±0.118^j,k	1.164±0.128^m,n
电针组	6	2.257±0.210	1.198±0.067^c	1.235±0.102^f	0.927±0.139ⁱ	0.795±0.090^l	0.696±0.038^o
F值		0.083	5.813	15.910	3.592	6.683	7.158
P值		0.969	0.005	< 0.001	0.032	0.001	0.012

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