摘要
目的:探讨脑灵汤对阿尔茨海默病(Alzheimer's,AD)模型大鼠学习记忆、病理形态及其对海马CA3区α4NachR和α7NachR表达的影响,并揭示AD发病的部分机理和为寻找中医药治疗AD提供可能的理论基础。
方法:选用清洁级SD大鼠经Y-迷宫测试后,选取30只,随机分为正常组、假手术组、模型组、西药组(多耐派齐组)和中药组(脑灵汤组),每组6只,喂养一周后,采用Apl-42注射大鼠海马法制成大鼠模型,再喂养30天,治疗后用Y-迷宫试验和Morris水迷宫检测大鼠学习记忆行为能力,用刚果红染色观察大鼠海马部位p-淀粉样蛋白沉积的情况,HE染色检测大鼠海马组织形态学变化。免疫组化法观察α4NachR、α7NachR在大鼠海马CA3区中的表达。
结果:1.Y-迷宫实验中,模型组大鼠所需的电击次数最多,与假手术组和正常组比较p<0.05,中药组、西药组两组大鼠所需的电击次数减少,与模型组相比p<0.05,且两治疗组相比无显著性差异(p>0.05)。2.Morris水迷宫隐匿平台搜索实验中,与假手术组和正常组比较,模型组大鼠表现为逃避潜伏期明显延长(p<0.01);探索实验中,正常组和假手术组动物的平均穿越次数最多,中药组和西药组动物穿越次数又多于模型组,比较有显著差异(p<0.01)。3.刚果红染色:正常组、假手术组大鼠海马切片在光镜下未见橘红色淀粉样沉积。模型组大鼠的海马切片上可见橘红色斑块状淀粉样沉积,说明模型组海马组织区有Ap沉淀。4.光镜观察显示,假手术组和正常组大鼠海马CA3区锥体细胞排列紧密整齐;模型组大鼠海马CA3区锥体细胞排列紊乱,有细胞缺失的现象,且正常锥体细胞数目较正常组和假手术组比较明显减少(p<0.05);两治疗组大鼠海马CA3区锥体细胞形态较模型组正常,排列较整齐,缺失的细胞少,更接近假手术组。5.α4NachR免疫组化结果显示,模型组大鼠海马CA3区域阳性细胞数最少,染色最浅。6.α7NachR免疫组化结果显示,各组大鼠海马CA3区α7NachR阳性细胞数比较,模型组最少,染色浅,正常组阳性细胞数最多,染色最深,而中药组、西药组阳性细胞数介于正常组及模型组之间。
结论:1.本实验研究中,采用Ap1-42注射大鼠海马制作的AD模型大鼠出现了AD的一些行为学和病理改变,说明成功建立了AD模型。2.AD模型大鼠的行为学能力明显下降,脑灵汤能改善模型大鼠的行为学能力。3.脑灵汤通过上调AD模型大鼠海马CA3区细胞膜上α7NachR、α4NachR的表达来达到预防和治疗AD的作用。
OBJECTIVE:To observe the effect of Naoling Decoction on ethology, hippocamal histomorphology,and expression of a4NachR and a7NachR in CA3 region of the rats with the model Alzheimer disease, and explore the therapeutical effect on Alzheimer disease rats and the potential mechanism of action of Naoling Decoction.
METHODS:After Y-electric-maze testing,chooseing thirty SD (spragu-dawleg) rats were classified into five groups:normal group, sham-operated group, model group,western medical group(donepezil group) and traditional Chinese drug group(Naoling Decoctio group). The Alzheimer disease model was established by Aβ1-42 injected into hippocamal in rats. The faculty of learning and memory was evaluated by Y-electric-maze test and Morris water maze experiment.The brain tissues were removed to be made frozen sections and stained with congored to detect the aggradation of Aβ,the changes of cell morphology were detected by HE stain. Expression of a4-NachR and a7-NachR in CA3 region was measured with immunohistochemical staining.
RESULTS:1.The results of Y-electric-maze test showed that compared with sham-operated group and normal group, model group's times to evade stimulate is more (P<0.05);compared with model group, Naoling Decoctio group and Piracetam group's times to evade stimulate is less(p<0.05). Meanwhile, there existed no obvious difference between these two therapy groups(p>0.05).2. The results of Morris water maze experiment showed that Compared with sham-operated group and normal group, the escaped and latent period of model group was delayed significantly (P<0.05). In exploratory experiment, the average pass through times in sham operation group and normal group were more than that of other three ones, and that of the model group was lest, there were significant difference (P<0.05). 3.Congored coloration result:Under the light microscope,in the hippocampal fields of rats in sham-operated group and normal group,orange amylaceous aggradation can’t be seen, the cells in DG arrange in order. In the hippocampal fields of rats in the model group, significant orange amylaceous aggradation can be seen in the area that injecting Aβ1-42,this denota there is aggradation of Aβin the hippocampal fields of rats in the model group,meanwhile,the cells in DG obviously damaged,neuron loss noticeable,and there is neuroglial cell proliferation.4.Under the light microscope, hippocampal CA3 fields of rats in the sham-operated group and normal group exhibited closely and neatly spaced pyramidal cells, and insignificant neuron loss;in the hippocampal CA3 fields of rats in the model group sparse and disturbed pyramidal cells,noticeable neuron loss and neuroglial cell proliferation could be seen,meanwhile,the number of pyramidal cells is less than sham-operated group and normal group(p<0.05). Neuron loss reduced significantly in the hippocampal CA3 pyramidal cell fields of the two therapy group and cell morphology presented relative normal.5.The result ofα4NachR with immunohistochemical staining denote the model one'masculine cells abouta4NachR was the least in hippocampal CA3 region,and their colour are darker than theirs.6.The result of a7NachR with immunohistochemical staining denote:the normal group,masculine cells abouta7NachR was the most in hippocampal CA3 region, their colour are darkerst.The Naoling Decoctio group and donepezil group had masculine cells between the model one and the normal group。
CONCLUSIONS:1.The presentation of results of the study that the model was established by Aβ1-42 injected into hippocamal was blest, because the model rats had the changes of praxiology and pathology.2.The learning and memory of the model rats were decreased obviously, Naoling Decoction can improve the learning and memory of the model rats.3.Naoling Decoction can increase the expression ofa4NachR anda7NachR in hippocampal CA3 of AD rats.
引文
[1]Cummings JL,Cole G.. Alzheimer disease. JAMA.2002,287:2335-2338
[2]Heppner FL, Gandy S, McLaurin J. Current concepts and future prospects for Alzheimer disease vaccines. Alzheimer Dis AssocDisord 2004;18:38-43.
[3]Marx J. New "Alzheimer's mouse" produced. Science (Washington D.C.) 1996; 273:50-53
[4]Pappas B A, Bayley P J, Bui B K, et al. Choline acetyltransferase activity and cognitive domain scores of Alzheimer's patients[J]. Neurobiol Aging,2000,21 (1):11.
[5]Tohgi H1Remarkable reduction in acetylcholine concentration in the cerebr-ospinal fluid from patientswith Alzheimer type dementia[J] Neurosci Lett,1994; 177(1):1392421
[6]SarterM, HasselmoM E, Bruno J P, et al. Unraveling the attentional functions of cortical cholinergic inputs:interactions between signal driven and cognitive modulation of signal detection[J]. Brain Res Rev,2005,48 (1):98
[7]Perry EK (1986) The cholinergic hypothesis-ten years on. Br Med Bull42:63-69
[8]石莎,殷明.烟碱型乙酰胆碱受体及其神经保护作用[J.]现代生物医学进展,(2009)07-1350-02
[9]Gotti C, Clementi F. Neuronal nicotinic recep tors:from structure to pathology[J]. Prog Neurobiol,2004,74 (6):3632396.
[10]Shun SHIMOHAMA, Nicotinic Receptor-Mediated Neuroprotection in Neurodegenerative Disease Models.[J]. Biol. Pharm. Bull.32(3) 332-336 (2009)
[11]Federico Dajas-Bailador and Susan Wonnacott.Nicotinic acetylcholine receptors and the regulation of neuronal signaling.[J].TRENDS in Pharmacological Sciences Vol.25 No.6 June 2004
[12]bert S. Bitner, Arthur L. Nikkel, et.al. Selectiveα7 nicotinic acetylcholine receptor activation regulates glycogen synthase kinase3β and decreases tau phosphorylation in vivo.[J].Elseier (2009) 65-74
[13]Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP,Reitz AB.β-amyloid(1-42) binds toa-7 nicotinic acetylcholine receptor with high affinity: Implications for Alzheimer's disease pathology. J Biol Chem2000; 275: 5626-32.
[14]uki TAKADA-TAKATORI, Toshiaki KUME, Yasuhiko IZUMI, et al.Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation.[J].Biol. Pharm. Bull.32(3) 318-324 (2009)
[15]徐叔云,卞如镰,陈修主编.药理实验方法学[M].北京:人民卫生出版社,1996,661-662
[16]张延霞.郭索君,崔瑞耀.骆刚,雌激素对穹隆海马伞切断大鼠脑内nAchR的干预作用.[J].临床军医杂志,2006年2月第34卷第1期.
[17]杨春,章茜,韦迎娜等.p-淀粉样蛋白致大鼠Alzheimer病模型的研究[J].河南医学研究,2003,12(4):294
[18]包新民.舒斯云.大鼠脑立体定位图谱[M].第Ⅰ版.北京:人民卫生出版社.1991.44-4
[19]王跃春.王子栋。孙黎明,等.动物学习记忆能力的Y-型迷宫测试法[J].暨南大学学报(自然科学版),2001,22(4):137-140
[20]徐叔云,卞如镰,陈修主编.药理实验方法学[M].北京:人民卫生出版社.2002:179-181,202-204,769-772,826-834)
[21]MORRIS R. Development of a water-maze procedure for study spatial learning in the rat[J]. J Neurosci 1984;(11):47-60
[22]王跃春,王子栋.大鼠Y-型迷宫测试指标正常值的确定[J].中国行为医学科学,2003,12(3):333
[23]张磊.张均田.学习、记忆的实验力法和记忆障碍模型[J].药学通报.1988,23(8):475-477
[24]徐斌,陈俊抛,等.两种改进的甲醇刚果红染色[J].临床与实验病理学杂志,2001,17(2):174
[25]Butterfield DA,How ard B, Yat in S, et al. Elevated oxidative stress in models of normal brain aging and Alzheimer's disease[J].L ife Sci,1999,65 (18):1883- 1892
[26]Chong Z Z,Li F.Maiese K.Stress in the brain:novel cellular mechanisms of injury linked to Alzheimer's disease[J].Brain Res Brain Res Rev.2005.49:1-21
[27]Bons N,Mestre N,Ritchie K,et al. Identification of amyloid-beta protein in the brain of the small, short-lived lemurian primate microcebus murinus[J]. Neuro-biol Aging,1994,15(2):215-220
[28]Itoh A, Nitta A,Nadai M,et al.Dysfunction of cholinergic and dopaminergic neuro-nal systems in beta-amyloid protein-infused rats[J].J Neurochem,1996, 66(3):1113-1117
[29]秦海强,李亚,田苏平,等.p-淀粉样蛋白及D-半乳糖对大鼠学习记忆和胆碱酯酶活性的影响.[J].南京医科大学学报,2000,20:195-19.
[30]R.M. Nitsch, B.E. Slack, R.J. Wurtman, J.H. Growdon, Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylc-holine receptors, Science 258 (1992)304-307.
[31]Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP,Reitz AB.β-amyloid (1-42) binds toa-7 nicotinic acetylcholine receptor with high affinity: Implica-tions for Alzheimer's disease pathology. J Biol Chem2000; 275:5626-32.
[32]Mousavi, E. Hellstrom-Lindahl.Nicotinic receptor agonists and antagonists increase sAPPa secretionand decrease Aβlevels in vitro.[J]. Neurochemistry International 54 (2009) 237-244
[33]Gotti, C., Clementi, F.,2004. Neuronal nicotinic receptors:from structure to pathology.Prog. Neurobiol.74,363-396.
[34]Gotti C, Moretti M, Bohr I, Ziabreva I, Vailati S, Longhi R, Riganti L, Gaimarri A,McKeith IG, Perry RH, et al. (2006) Selective nicotinic acetylcholine receptor subunit deficits identified in Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies by immunoprecipitation. Neurobiol Dis 23:481-489.
[35]Pimlott SL, Piggott M, Owens J, Greally E, Court JA, Jaros E, Perry RH, Perry EK,and Wyper D (2004) Nicotinic acetylcholine receptor distribution in Alzheimer'sdisease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia:in vitro binding study using 5-[125I]-A-85380. Neuropsycho-pharmacology 29:108-116.
[36]Cout J. Nicotinic receptor abnormalities in Alzheimer's disease[J]. Biological Psychiatry,2001,49:175-84.
[37]陈燕,赵春玲,烟碱型乙酰胆碱受体在认知功能中的作用[J].国际病理科学与临床杂志,2008,28(2):0142-05
[38]Klink R, Exacede AdK, Zoli M, et all Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei [J] Neurosci,2001,21:1452-14631
[39]Bitner, R.S., Bunnelle, W.H., Anderson, D.J., Briggs, C.A., Buccafusco, J., Curzon, P., Decker, M.W., Frost, J.M., Gronlien,J.H., Gubbins, E., Li, J., Malysz, J., Markosyan, S., Marsh, K., Meyer, M.D., Nikkel, A.L., Radek, R.J., Robb, H.M., Timmermann, D., Sullivan, J.P., Gopalakrishnan, M.. Broad-spectrum, efficacy across cognitive domains by alpha7 nicotinic,acetylcholine receptor agonism correlates with activation of,ERK1/2 and CREB phosphorylation pathways. [J]. Neurosci. (2007) 27,10578-10587.
[40]Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, and Akaike A(2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51:474-486
[41]Hooper, C., Killick, R., Lovestone, S. The GSK3 hypothesis ofAlzheimer's disease. J. Neurochem. (2008) 104,1433-1439.
[42]wang H,Yu M,Ochani M,etal,Nicotinic acetylcholine receptor alpha7 subuint is an essential regulator of inflammation. nature,2003,421:384-388.
[43]卫培峰,焦晨莉,陈丹丹.何首乌现代药理研究进展.[J].现代中医药2004年第1期,57-58
[44]李振国,杨期东,AD大鼠淀粉样蛋白前体裂解酶的改变及其机制的实验研究,中南大学博十论文.2006-0501
[45]周琳,杨期东等.何首乌对淀粉样p蛋白致海马神经元的凋亡和学习记忆障碍的作用.[J].中国临床康复第9卷第9期2005-03-07
[46]姜文华,孟晓婷,郝利铭,等.红景天素抗老化和抗痴呆效应的实验研究[J]白求恩医科大学学报,2001,27(2):127-129.
[47]王健,李丽,曹娟等.红景天对AD大鼠空间学习记忆能力及海马组织CAT、GSH-Px的影响.[J].中国中医急症2008年12月第17卷第12期.
[48]王晓英,陈雯等.人参皂苷Rgl对A β(25-35)侧脑室注射小鼠记忆障碍的改善作用及机制.药学学报,2001,36(1):1-4
[49]谭赛辉,杨剑钢.脑灵汤对阿尔茨海默病模型大鼠海马CA3区域GFAP和IL-1p表达的影响[J].中南大学,2007:30-31
[50]罗红波,何明大.脑灵汤对AD模型大鼠学习记忆及海马老年斑的影响.[J].中国行为医学科学.2005,14(7)599-600
[51]脑灵汤对阿尔茨海默病模型鼠脑凋亡调控基因的影响.[J].中国现代医学杂志,2005,15(22)3398-3401
[52]葛小平,苏南湘.脑灵汤对阿尔茨海默病大鼠TGFβ1及TNFa的影响.[J].中南大学,2007
[53]钟炳武,何明大.脑灵汤对阿尔茨海默病大鼠海马CA3区APPiNOS表达的影响.[J].中南大学,200703
[54]Seow D,Uauthier S.Pharmacotherapy of Alzheimer disease [J]. Can J Psychiatry. 2007.52:620-629
[55]刘运林,何明大,周泽泉.脑灵汤对阿尔茨海默病的血脂及血流变的影响.[J].中国血流变学杂志,2006;16(1)。
[1]蔡建光.阿尔茨海默病主要相关基因及其功能蛋白研究进展[J].中国神经免疫学和神经病学杂志,2006,3(2):120
[2]Nordberg A.Neuroreceptor changes in Alzheimer disease J. Cerebrovasc Brain Metab Rev,1992,4(4):303-328
[3]石莎,殷明.烟碱型乙酰胆碱受体及其神经保护作用[J.]现代生物医学进展,(2009)07-1350-02
[4]Dajas2Bailador F, Wonnacott S. Nicotinic acetylcholine receptersand the regul-ation of neuronal signaling[J]. Trends PharmacolSci,2004,25(6):317324.
[5]陈燕,赵春玲,烟碱型乙酰胆碱受体在认知功能中的作用[J].国际病理科学与临床杂志,2008,28(2):0142-05
[6]Yuki TAKADA-TAKATORI, Toshiaki KUME,et. Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation.J. Biol. Pharm. Bull.32(3) 318-324 (2009)
[7]MousaviM, Hellstrom-Lindahl E. Protein and mRNA levels of nicotinic receptors in brain of tobacco using controls and patients with Alzheimer's disease [J]. Neuroscience,2003,122:515
[8]WeversA, Schroder H. Nicotinic acetylcholine receptors in Alzheimer's disease [J]. J A lzheim er's D is,1999,1:207
[9]Hellstrom-Lindahl E,MousaviM. Regional distribution of nicotinic receptor subunit mRNAs in human brain:comparison between Alzheimer and normal brain [J]. M ol. B rain. Res,1999,66:94
[10]Nordberg A,Lundkvist H. Kinetic analysis of regional (S)(-) 11C-nicotine binding in normal and Alzheimer brain-in vivo assessmentusing positron emiss-ion tomography [J]. A lzheim er D is AssoDisord,1995,9:21
[11]Flores CM. A subtype of nicotinic cholinergic receptor in rat brainis composed of alpha4 and beta2 subunits and is up regulated by chronic nicotine treatment[J]. Mol Ph arm aco,1992,41:31
[12]Molinari EJ. Up-regulation of human alpha7 nicotinic receptor by chronic treatment with activator and antagonist ligands.[J]. Eu ro JPha rm aco,1998, 347:131
[13]Buisson B. Chronic exposure to nicotine up-regulates the human alpha4beta2 nicotinic acetylcholine receptor function [J]. J N eu rosci,2001,21:1819
[14]Fernandes C, Hoyle E, Demp ster E, et al. Performance deficit of alpha? nicotinic receptor knockout mice in a delayed matching to p lace task suggests a mild impairment of working/ ep isodic-like memory[J]. Genes Brain Behav,2006,5 (6):433-440.
[15]Pocivavsek A, Icenogle L, Levin ED. Ventral hippocampal alpha7and alpha4-beta2 nicotinic receptor blockade and clozapine effectson memory in female rats[J]. Psychopharmacology (Berl),2006,188 (4):597-604
[16]Fu W, Jhamandas JH. β-Amyloid peptide activates non-α7 nicotinicacetylcholine receptors in rat basal forebrain neurons. J。 Neurophysiol 2003; 90:3130 6.
[17]Wang HY, Lee DH, D'Andrea MR, Peterson PA, Shank RP,Reitz AB.β-amyloid (1-42) binds toa-7 nicotinic acetylcholine receptor with high affinity: Implica tions for Alzheimer's disease pathology. J Biol Chem 2000; 275:5626 32.
[18]Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P,Labarca C, et al. Nicotine activation of a4 receptors:sufficient for reward, tolerance, and sensitization. Science 2004; 306:1029-32.
[19]Dineley KT, Bell KA, Bui D, Sweatt JD. β-Amyloid peptide activatesa7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 2002; 277:25056 61.
[20]Nagele RG, D'Andrea MR, Anderson WJ, Wang HY. Intracellularaccumulation of β-amyloid(1-42) in neurons is facilitated by thea-7 nicotinic acetylcholine receptor in Alzheimer's disease.Neuroscience 2002; 110:199 211.
[21]Michael R, D'Andrea, Daniel HSL, Wang HY, Nagele RG. Targeting intracellular Aβ1-42 for Alzheimer's disease. drug discovery.Drug Dev Res 2002; 56:194 200
[22]Qiang LIU, Jie WU. Neuronal nicotinic acetylcholine receptors serve as sensitive targets that mediate-β-aloid neurotoxicity.[J]. Acta Pharmacologica Sinica 2006 Oct;27(10):1277-1286
[23]Lamb PW, Melton MA, Yakel JL. Inhibition of neuronal nicotinicacetylcholine receptor channels expressed in Xenopus oocytesbyβ-amyloid1-42 peptide. J Mol Neurosci 2005; 27:13 21.
[24]杨荣军,万琪,高中宝,耿晓英.p淀粉样蛋白对神经元上烟碱型乙酰胆碱受体β2亚单位表达的影响[J].中华老年心脑血管病杂志,1009-0126(2006)04-026-04
[25]M. M. Hedberg, M. M. svedberg, T. Mustafiz,w.-f. yu, M. mousavi, Z.-Z. guan, c. ungerand a. nordberg transgenic mice overexpressing human acetylcholines-terase and the swedish amyloid precursor protein mutation:effect of nicotine treatment.[j]. neuroscience 152 (2008) 223-233
[26]Mousavi, E. Hellstrom-Lindahl.Nicotinic receptor agonists and antagonists increase sAPPa secretionand decrease Aβlevels in vitro.[J]. Neurochemistry International 54 (2009) 237-244
[27]Finch CE,Morgan TE. systemic inflammation, infection, ApoE alleles, and Alzheimer's disease:a position paper [J]. Curr Alzheimer Res,2007,4 (2) 1852189
[28]Nagele RG,D'Andrea MR, Lee H, et al. Astrocytes accumulate A-betal- 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains[J]. Brain Res,2003,971 (2):197-209.
[29]Jen LS, Hast AJ, Jen A, et al. Alzheimer's petide kills of retina in vivo[J]. Nature, 1998,392(6672):140-141.
[30]Savage MJ, Lin YG, Ciallella JR, et al. Activation of c-Jun N-Terminal kinase and p38 in an Alzheimer's diseasemodel is associatedwith amyloid deposition [J]. Neurosci,2002,22 (9):3376-3385
[31]王妍,张忠义,王勇,α7-nAChR在海马星形胶质细胞上的表达[J].南方医科大学学报(J South Med Univ),1673-4254(2007)05-0591-04
[32]雷露雯,王勇,小胶质细胞α7-nAChR表达及意义.[J].山东医药,1002-266X(2008)48-0001-02
[33]Federico Dajas-Bailador, Susan Wonnacott, Nicotinic acetylcholine receptors andthe regulation of neuronal signalling.[J]. Trends in Pharmacological Sciences Vol.25 No.6 June 2004
[34]Xin M and Deng X (2005) Nicotine inactivation of the proapoptotic function of Bax through phosphorylation. J Biol Chem 280:10781-10789
[35]Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, and Akaike A(2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51:474-486
[36]Ren K, Puig V, Papke RL, Itoh Y, Hughes JA, and Meyer EM (2005) Multiple calciumchannels and kinases mediate _7 nicotinic receptor neuroprotection in PC12 cells. J Neurochem 94:926-933.
[37]H.Royden Jones《netter'neurology 》 312-331(2009)
[38]uki TAKADA-TAKATORI, Toshiaki KUME, Yasuhiko IZUMI, et al.Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation.[J].Biol. Pharm. Bull.32(3) 318-324 (2009)
[39]Katy A. Chalmers Gordon K. Wilcock. Et al. Cholinesterase inhibitors may increase phosphorylated tau in Alzheimer's disease.[J]. J Neurol (2009) 256:717-720
[40]ddo S, Caccamo A, Green KN, Liang K, Tran L, Chen Y, Leslie FM, LaFerla FM (2005) Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer'sdisease. Proc Natl Acad Sci USA 102:3046-3051
[41]bert S. Bitner, Arthur L. Nikkel, et.al. Selectivea7 nicotinic acetylcholine receptor activation regulates glycogen synthase kinase3β and decreases tau phosphorylation in vivo.[J].Elseier (2009) 65-74
[42]Cherie E. Bond, Martina Zimmermann, Susan A. Greenfield1。 Upregulation of a7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides [J] PLoS ONE| www.plosone.org March 2009| Volume 4| Issue 3| e4846
[43]Robyn Carson,David Craig,Dominic Hart,Stephen Todd. Et al. Genetic
Variation in the α7 Nicotinic Acetylcholine Receptor is Associated with Delusional Symptoms in Alzheimer's Disease.[J]. Neuromol Med (2008) 10:377-384