脑灵汤对阿尔茨海默病模型大鼠海马CA3区域GSK-3β与P-CREB表达的影响
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摘要
目的:观察脑灵汤对阿尔茨海默病模型大鼠行为学、海马组织形态学、海马CA3区GSK-3β和P-CREB蛋白表达的影响,初步探讨脑灵汤对AD模型大鼠的治疗作用及其可能的作用机制。
方法:将经Y型迷宫测试筛选后入选的40只SD大鼠完全随机分为正常组、假手术组、模型组、中药组和西药组。采用Aβ1-42注射大鼠海马制作AD大鼠模型,Y迷宫试验和Morris水迷宫测定大鼠造模后三周的学习记忆成绩,取脑组织作冰冻切片,刚果红染色观察大鼠海马是否有β-淀粉样蛋白的沉积,HE染色、Nissl染色观察大鼠海马组织形态学改变。免疫组化法观察GSK-3β和P-CREB在大鼠海马CA3区组织神经元中的表达。
结果:(1)Y迷宫实验中,与假手术组和正常组比较,模型组大鼠学会躲避所需的电刺激次数明显增多(p＜0.05),与模型组比较,经药物干预后,中药、西药两治疗组大鼠表现为所需的电刺激次数减少(p＜0.05),且两治疗组相比无显著性差异。(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＜0.05);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＜0.05)。(3)刚果红染色:光镜下,正常组、假手术组大鼠海马切片未见橘红色淀粉样沉积,海马背侧细胞带排列整齐。模型组大鼠Aβ1-42注射部位的海马切片上可见橘红色斑块状淀粉样沉积,提示海马组织区有Aβ沉淀,且模型组海马背侧细胞带明显损伤,局部神经元大段缺失,并出现胶质细胞反应。(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,无明显神经元脱失;模型组大鼠海马CA3区锥体细胞排列稀疏、紊乱,神经元脱失明显,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);中、西药治疗组大鼠海马CA3区神经元脱失现象明显减轻,锥体细胞形态较正常,排列较整齐,接近假手术组。(5)GSK-3β免疫组化结果显示,各组大鼠海CA3区域GSK-3β阳性细胞数比较,模型组最多,中药组和西药组高于正常组和假手术组(p＜0.05),具有统计学意义。灰度值比较结果显示,模型组显著高于正常组与假手术组,而中药组与西药组低于模型组(P＜0.05),具有统计学意义。(6)P-CREB免疫组化结果显示,各组大鼠海马CA3区P-CREB阳性细胞数比较,模型组最少,中药组和西药组低于正常组和假手术组(p＜0.05),具有统计学意义。各组大鼠海马CA3区P-CREB灰度值比较,模型组显著低于假手术组和正常组(p＜0.05);中药组和西药组大鼠海马CA3区P-CREB灰度值较模型组显著增加(p＜0.05)。
结论:(1)本实验研究结果表明采用Aβ1-42注射大鼠海马制作AD模型大鼠出现了AD的一些行为学及病理改变,说明该模型的建立是成功的。(2)AD模型大鼠学习记忆能力明显下降,脑灵汤能提高模型大鼠的学习记忆能力。(3)脑灵汤能减轻AD大鼠海马CA3区神经元脱失现象,改善AD大鼠海马锥体细胞形态,对AD大鼠有治疗作用。(4)脑灵汤可降低AD大鼠海马CA3区GSK-3β的表达,提高P-CREB水平,这些可能是脑灵汤治疗阿尔茨海默病的部分作用机制。
Objective:To observe the effect of Naoling Decoction on ethology, hippocamal histomorphology,and expression of GSK-3βand P-CREB in CA3 region of the rats with synthetic Alzheimer disease,and explore the therapeutical effect on Alzheimer disease rats and the potential mechanism of action of Naoling Decoction.
Methods:Forty SD(spragu-dawleg)rats were classified into five groups after Y-electric-maze testing:normal group,sham- operated group, model group,Naoling Decoctio group and Piracetam 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 after establishing AD model.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 and Nissl stain.Expression of GSK-3β,P-CREB 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 of GSK-3βwith immunohistochemical staining denote:The compasion of masculine cells about GSK-3βin each group of hippocampal CA3,the model one was the most,the Naoling Decoction group and Piracetam group were more than sham-operated group and normal group(p＜0.05).They had statistical significance.The compasion of the gray scale value about GSK-3βin hippocampal CA3 of each group,the model group were higher than sham-operated group and normal group(p＜0.05);the gray scale value of Naoling Decoction group and Piracetam group were lower than the model group's gray scale value(p＜0.05).(6)The result of P-CREB with immunohistochemical staining denote:The compasion of masculine cells about P-CREB in hippocampal CA3,of each group,the model one was the least,the Naoling Decoction group and Piracetam group were more than the model group(p＜0.05),They had statistical significance..The compasion of the gray scale value about P-CREB in hippocampal CA3 of each group,the model group were lower than sham-operated group and normal group (p＜0.05);the gray scale value of Naoling Decoction group and Piracetam group were higher than the model group's gray scale value(p＜0.05).
CONCLUTIONS:(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 dcrease neuronal loss and better pathomorphological changes in hippocampal CA3 of AD rats,thusly it has therapeutic action on vascular dementia rats.(4)Naoxintong capsule can weaken the expression of GSK-3βin hippocampal CA3 of AD rats,Elevate the expression of P-CREB,those partly may be therapeutic mechanism on Alzheimer disease of Naoling Decoction.
方法:将经Y型迷宫测试筛选后入选的40只SD大鼠完全随机分为正常组、假手术组、模型组、中药组和西药组。采用Aβ1-42注射大鼠海马制作AD大鼠模型,Y迷宫试验和Morris水迷宫测定大鼠造模后三周的学习记忆成绩,取脑组织作冰冻切片,刚果红染色观察大鼠海马是否有β-淀粉样蛋白的沉积,HE染色、Nissl染色观察大鼠海马组织形态学改变。免疫组化法观察GSK-3β和P-CREB在大鼠海马CA3区组织神经元中的表达。
结果:(1)Y迷宫实验中,与假手术组和正常组比较,模型组大鼠学会躲避所需的电刺激次数明显增多(p＜0.05),与模型组比较,经药物干预后,中药、西药两治疗组大鼠表现为所需的电刺激次数减少(p＜0.05),且两治疗组相比无显著性差异。(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＜0.05);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＜0.05)。(3)刚果红染色:光镜下,正常组、假手术组大鼠海马切片未见橘红色淀粉样沉积,海马背侧细胞带排列整齐。模型组大鼠Aβ1-42注射部位的海马切片上可见橘红色斑块状淀粉样沉积,提示海马组织区有Aβ沉淀,且模型组海马背侧细胞带明显损伤,局部神经元大段缺失,并出现胶质细胞反应。(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,无明显神经元脱失;模型组大鼠海马CA3区锥体细胞排列稀疏、紊乱,神经元脱失明显,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);中、西药治疗组大鼠海马CA3区神经元脱失现象明显减轻,锥体细胞形态较正常,排列较整齐,接近假手术组。(5)GSK-3β免疫组化结果显示,各组大鼠海CA3区域GSK-3β阳性细胞数比较,模型组最多,中药组和西药组高于正常组和假手术组(p＜0.05),具有统计学意义。灰度值比较结果显示,模型组显著高于正常组与假手术组,而中药组与西药组低于模型组(P＜0.05),具有统计学意义。(6)P-CREB免疫组化结果显示,各组大鼠海马CA3区P-CREB阳性细胞数比较,模型组最少,中药组和西药组低于正常组和假手术组(p＜0.05),具有统计学意义。各组大鼠海马CA3区P-CREB灰度值比较,模型组显著低于假手术组和正常组(p＜0.05);中药组和西药组大鼠海马CA3区P-CREB灰度值较模型组显著增加(p＜0.05)。
结论:(1)本实验研究结果表明采用Aβ1-42注射大鼠海马制作AD模型大鼠出现了AD的一些行为学及病理改变,说明该模型的建立是成功的。(2)AD模型大鼠学习记忆能力明显下降,脑灵汤能提高模型大鼠的学习记忆能力。(3)脑灵汤能减轻AD大鼠海马CA3区神经元脱失现象,改善AD大鼠海马锥体细胞形态,对AD大鼠有治疗作用。(4)脑灵汤可降低AD大鼠海马CA3区GSK-3β的表达,提高P-CREB水平,这些可能是脑灵汤治疗阿尔茨海默病的部分作用机制。
Objective:To observe the effect of Naoling Decoction on ethology, hippocamal histomorphology,and expression of GSK-3βand P-CREB in CA3 region of the rats with synthetic Alzheimer disease,and explore the therapeutical effect on Alzheimer disease rats and the potential mechanism of action of Naoling Decoction.
Methods:Forty SD(spragu-dawleg)rats were classified into five groups after Y-electric-maze testing:normal group,sham- operated group, model group,Naoling Decoctio group and Piracetam 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 after establishing AD model.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 and Nissl stain.Expression of GSK-3β,P-CREB 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 of GSK-3βwith immunohistochemical staining denote:The compasion of masculine cells about GSK-3βin each group of hippocampal CA3,the model one was the most,the Naoling Decoction group and Piracetam group were more than sham-operated group and normal group(p＜0.05).They had statistical significance.The compasion of the gray scale value about GSK-3βin hippocampal CA3 of each group,the model group were higher than sham-operated group and normal group(p＜0.05);the gray scale value of Naoling Decoction group and Piracetam group were lower than the model group's gray scale value(p＜0.05).(6)The result of P-CREB with immunohistochemical staining denote:The compasion of masculine cells about P-CREB in hippocampal CA3,of each group,the model one was the least,the Naoling Decoction group and Piracetam group were more than the model group(p＜0.05),They had statistical significance..The compasion of the gray scale value about P-CREB in hippocampal CA3 of each group,the model group were lower than sham-operated group and normal group (p＜0.05);the gray scale value of Naoling Decoction group and Piracetam group were higher than the model group's gray scale value(p＜0.05).
CONCLUTIONS:(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 dcrease neuronal loss and better pathomorphological changes in hippocampal CA3 of AD rats,thusly it has therapeutic action on vascular dementia rats.(4)Naoxintong capsule can weaken the expression of GSK-3βin hippocampal CA3 of AD rats,Elevate the expression of P-CREB,those partly may be therapeutic mechanism on Alzheimer disease of Naoling Decoction.
引文
[1]孙绪举,许明望.阿尔茨海默症治疗药物的研究进展[J].中国医院药志,2003,23(6):364-365.
[2]何燕.中药多糖的免疫调节作用[J].四川中医,2001,19(2):15-17.
[3]BayerTA,Wirths O,Majtenyik,etal.Key factors in Alzhermer's diseases:beta-amyloid precursor protein processing,metabolism and traneuronaltransport.Brain Pathol 2003;11(1):1-4.
[4]John H.M.& Patrick R.H.Life death of neurons in the aging brain.Science 2003,278(9):412-416.
[5]Maccioni B.R,Munoz P.J.&Barbeito L.The molecular bases of Alzheimer's disease and other neurodegenerative disases.Archives of Medical Research 2002;32(6):81.
[6]Henderson V.W.,et al.The neurobiology of Alzheimer's desease.J Neurosur 1998;70(12):335-337.
[7]郭文平,付欣鸽,倪振贤.Aβ25-35对培养大鼠大脑皮质和海马神经元存活和生长的影响[J].农垦医学,1999,21(4):242.
[8]Bayer TA,Wirths O,Majtenyik,etal.Key factors in Alzheimer's disease:betaamyloid precursor protein processing,metabolism and intraneuronaltransport.Brain Pathol 2003;11(1):1-5.
[9]Grimes C A,Jope R S.The multifaceted roles of glycogen Requirement for synthase kinase 3b in cellular signaling.Prog Neurobiol,2001,65:391-426.
[10 Woodgett J R.Judging a protein by more than its name:GSK-3.Sci STKE,2001,100:RE12.
[11]Woodgett J R.Molecular cloning and expression of glycogensynthase kinase-3/factor A.EMBO J,1990,9:2431-2438.
[12]Flaherty B.D,Soria P.J,Tomasiewicz H.G et al Phosphotylation of human tau protein by microtubule-associated kinases:Gsk-3beta and cdk5 are key participants.J.Neurosi.62:463-472.
[13]Fath T,Eidenmuller J.and Brandt R.Tau-mediated cytotoxicity in pseudohyperphosphotylation model of Alzheimer's disease.J.neurosci.22:9733-9741.
[14]Ilouz R,Kowalsman N,Eisenstein M.Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition.J Biol Chem.2006 Oct 13;281(41):30621-30.
[15]江刚,舒斯云,包新民。CREB与中枢学习记忆功能的关系[J]。中国临床康复,2004,8(1):124-6.
[16]Lonze BE,Glnty DD,Function and regulation of CREB family transcription faors in the nervous system.Neuron 2002;35(4):605-3.
[17]Meng Y,Xu H,Wang R,et al.Impainment of singal transduction pathway on neuronal survival in brains of Alzheimers disease[J].zhonghua bing Li Xue Za Zhi,2002,31:502-5.
[18]Liang Z,Liu F,Grundke-Iqbal I,Down-regulation of cAMP-dependent protein kinase in Alzheimer disease brain.J Neurochem.2005 Dec;103(6):2462-70.Epub 2007 Oct 1.
[19]包新民,舒斯云.大鼠脑立体定位图谱.北京:人民卫生出版社,1991.44.
[20]Selkoe JD.Amyloid protein and Alzheimer's disease[J].Scientific American,1991,265(5):68.
[21]Masters CL,Simms G.Weinman NA,et al.Amyloid plaque core protein in Alzheimer's disease and down syndrome[J].Proc Natl Acad Sci USA,1985,82:4245.
[22]Mullan M.Crawford F.Genetic and molecular advances in Alzheimer's disease[J].Trends Neurosci,1993,16:398.
[23]Cotton P.Constellation of risks and processes seen in search for Alzheimer's disease[J].JAMA,1994,271(2):89.
[24]Cosgays JM,Latasa MJ,Pascua IA.Nerve growth factor and ras regulate beta-amyloid precusor protein gene expression in PC12 cells[J].J Neurochem,1996,67(1):98.
[25]Dvis K L,Thal L J,Garmzu ER,et al.A double-blind,placebo-controlled multicenter study of tacrine for Alzheimer's disease[J].New Engl J Med,1992,327(8):1253.
[26]胡桃英.论痴呆与痰凝血淤的关系.湖南中医药导报.1997,3(2):8-9.
[27]李海涛,曾莉.祖国医学对老年痴呆症的认识与研究.中医药学刊,2004,3:12-14
[W]胡桃英.论痴呆与痰凝血淤的关系.湖南中医药导报.1997,3(2):8-9.
[28]郭苏云,张映梅.补肾益脑为主治疗老年性痴呆.云南中医学院学报.2003,26(1):40-41.
[29]刘辉,陈俊抛,田时雨,等.Aβ1-40海马注射对大鼠脑内一氧化氮合酶表达的影响.中华神经科杂志[J],2001,34(2):92-95.
[30]Giovannelli L,Casamenti F,Scali C,et al.Differential effects of amyloid peptides beta-(1-40)and beta-(25-35)injections into the rat nucleus basalis.Neuroscience.1995,66(4):781-792.
[31]刘辉,陈俊抛,田时雨,等.海马注射β淀粉样蛋白对大鼠学习记忆及局部神经元的损伤作用.中华神经科杂志[J],2000,33(3):150-152.
[32]许士凯.抗衰老药物学.北京:中国医药科技出版社,1994.219-285.
[33]柯尊记,姚志杉.空间学习记忆的行为模式及其分子神经生物学基础[J].解剖科学进展,1998,4(1):1-7.
[34]Morris R GM.Developments of a water maze procedure for studying,spatial learning in the rat[J].J Neruo Sci Meth,1984,11:47.
[35]Delacourte A,Buee L.Tau pathology:neurodegenerative disorders.Curr.Op in.Neuro,2002,13,3712-3761.
[36]NielsA,Camilla H,Pia D,etal.Cerebrospianl fluidβ-Amyloid(1-42)in Alzheimerdisease[J].Arch Neurol,1999,56:673-680.
[37]王德生,张守信.老年性痴呆.北京:人民卫生出版社,2002:28-32.
[38]Bayer TA,Wirths O,Majtenyik,etal.Key factors in Alzhermer's diseases:betaamyloid precursor protein processing,metabolism traneuronal transport.Brain Pathol 2003;11(1):1.
[39]John H.M.& Patrick R.H.Life death of neurons in the aging brain.Science 2003;278(9):412-416.
[40]Flaherty B.D,Soria P.J,Tomasiewicz H.G et al Phosphotylation of human tau protein by microtubule-associated kinases:Gsk-3beta and cdk5 are key participants.J.Neurosi.62:463-472.
[41]Fath T,Eidenmuller J.and Brandt R.Tau-mediated cytotoxicity in pseudohyperphosphotylation model of Alzheimer's disease.J.neurosci.22:9733-9741.
[42]Hansen TO,Rehfeld JF,Nielsen FC.GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding.Neuroreport.2004Apr 9;15(5):841-5.
[43]CREB DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium.J Neurochem.2001 September;78(6):1219-1232.
[44]Leutgeb J K,Frey J U,Behnisch T.Single cell analysis of activity-dependent cyclic AMP-responsive element-binding protein phosphrylation long-lasting long-term potentiation in area CA1.
[45]Sambamurti K,Kinsey R,Maloney B,et al.Gene structure and organization of the human beta-seceretase(BACE)promoter[J].FASEB J,2004,18:1.34-6.
[46]Meng Y,Xu H,Wang R,et al.Impairment of signal transduction pathway on neuronal survival in brains of Alzheimers disease[J].zhonghua Bing Li Xue Za zhi,2002,31:5.2-5.
[47]傅仁杰.老年呆病的诊断、辨证分型及疗效评定标准(讨论稿)[J].中医杂志,1991,32(1):56.
[48]李海涛,曾莉.祖国医学对老年痴呆症的认识与研究[J].中医药学刊,2004,3:121.
[49]徐江平,杨雪梅。中草药活性成分防治阿尔采末病的研究进展[J]。第一军医大学学报,2001,1:23-26.
[50]张丹参,张均田。人参皂苷对大鼠海马齿状回突传递活动的影响[J]。药学学报,2000,35(3):185-188.
[51]陈晓光,崔志勇,等.何首乌对老年小鼠衰老指标的影响[J].中草药,191,22(8):359.
[52]Y angZ H.R ecentre searchs ituationo fan ti-agingr eactiono f Po lyg on um m ultiflorum Thunb.[J].L ishixhenM edM ater Me d R e s(时珍国医国药),1999,10(5):3 90-391.
[53]杨永昌.藏药志[M],西宁:青海人民出版社,1991:34.
[54]姜文华,王淑兰,关桂梅,红景天素对大鼠中枢神经系统的抗衰老作用的实验研究[J],白求恩医科大学学报,1959,21(1):8.
[55]zhang ZJ,Jiang W,Wan Q.Effect of rhodiola on lipidpenroxides and ultrastructure of mitochondria in the brain of senile mice[J].chin J clin Rehabil,2005;9(9):235-7.
[56]钱彦丛,秦葵,刘景东.红景天的化学及药理研究[J].北京军区医药,199;6(11):452-4.
[57]黄兆胜。中药对老年性痴呆中枢神经系统作用研究进展。[J]广州中医药大学学报,2000,(2):21-24.
[58]王月芳,万海同。论肾虚痰凝血瘀是老年性痴呆的重要发病机制[J]。中国中医基础杂志,2001,5(8):9-10.
[59]刘运林,何明大,周泽.脑灵汤对阿尔茨海默病血脂血流变的影响[J].中国血液流变学杂志.2006;16(1):69-71.
[60]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.
[61]Cotman CW,Tenner AJ,Cummings BJ.Beta-Amyloid converts anacute phase injury response to chronic injury responses.Neurobiol Aging,1996,17:723-731.
[62]何明大,刘运林。脑灵汤对阿尔茨海默病模型鼠凋亡调控基因的影响。中国现代医学杂志,2005,15(22)3398-3401.
[63]谭赛辉,杨建钢。脑灵汤对阿尔茨海默病模型大鼠海马CA3区域GFAP和IL-1β表达的影响,待发表.
[64]Delacourte A,Buee L.Tau pathology:neurodegenerative disorders.Curr.Opin.Neuro,2002,13,371-376.
[1]Cleveland DW,Hwo SY,Kirschner MW.Physical and chem-ical properties of purified tau factor and the role of tau in micro-tubule assembly.J Mol Biol,1977,116:227.
[2]Biernat J,Gustke N,Drewes G,et al.Phosphorylation of Ser262strongly reduces binding of tau to microtubules:distinc-tion between PHF-like immunoreactivity and microtubulebind-ing.Neuron,1993,11:153.
[3]Arend T.Neurogeneration and plasticity.INT.J.Dev.Neurosci.2004,22:9733-9741.
[4]Blennow K,Vanmechelen E,Hampel H.CSF total tau,Abe-ta42 and phosphorylated tau protein as biomarkers forAlzheimer's disease.Mol Neurobiol,2001,24(1-3):87.
[5]Ishiguro K,Omori A,Takamastsu M,et al.Phosphorylation sites on tau by tau protein kinase 1,a bovine derived kinase generating an epitope of paired helical filaments.Nuerosci.Lett.148:202-206.
[6]Lucas J.J,Hemandez E,Gomez-Ramos P.,et al.Decreased nuclear beta-catenin R,tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.EMBOJ.2001,20:27-39.
[7]周洁,陈娟,肖志宏等。载断型载脂蛋白E4对培养神经元细胞中神经细丝磷酸化的影响。[J]。中国临床康复。2006,10(46):209-211.
[8]Kim S.H.,Kim M.E.,Lee p.J.,et al.C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glyloid synthase kinase-3beta expression.FASEB J.2005,17:1951-1953.
[9]Gao Y.and Pimplikar S.W.The gamma-secretase-cleaved C-terminal framment of amyloid precursor protein mediates sinaling to the nucleus.Pros Natl.Acad.sci.USA 2001,98:14979-14984.
[10]Ryan K.A and pimplikar S.W.Activatiom of GSK-3 and phosphorylation of CRMP-2 in transgenic mice expressing APP intracellular domain.J,cell.Biol.2005,171:327-335.
[11] Su Y.,Ryder J.,LiB.,wu x.et al. Lithium,a commom drug for bipolar "disorder treatment,regulates amyloid-beta precursor protein processing,Biochemistry 2004,43:6899-6908.
[12] E.H.Karran,D.Allsop,GChristie,et al.Presenilins in searth of functionally. Biochemical societu Transactions,1992,23(3):491-496.
[13] Weihl,Ye Y.Ghadge D.G,Kennedy Gs .Mutant presenilin-1 induces apoptosis and downregulates AKT/PKB.J Neurosci.l999,19:5360-5369.
[14] Baki L,shioi J,Shao Z,Schwarxman A,et al.(2004)PSl activates PI3K thus inhibiting GSK-3 activity and Tau overphosphorylation:effects of FAD mutations. EMBO J.2004,23:2586-2596.
[15] Takachima A,Murayama M,Murayama.et al.(1998)presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.Proc.Natl.Acad. Sci.USA.1998,23:9637-9641.
[16] Pigna G,Morfini G,pelsman A,Mattson P.M and Busciglio J.Alzheimer's presenilin 1 mutations impair kinase based axonal transport.J.Neurosci. 2003, 23:4499-4508.
[17] Kirschenbaum F,Hsu c.s,Cordell B and McCarthy J.V. Substitution of a glycogen synthase kinase-3 beta phosphorylation site in the presenlin 1 seperates presenilin function from beta-catenin signaling .J.Biol.chen.2001,276:7366- 7375.
[18] Kirschenbaum F.,Hsu c s ,cordell B,and MdCarthy J.V.Glycogen synthase kinase-3 beta regulaes presenilin 1 c-terminal fragment levels.J.Biol.chem. 2001, 276:30701-30707.
[19] Pap M.and Cooper GM.Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival patyway.J.Biol.chem. 1998,273: 19929-19932.
[20] Grimes C.A.and Jope R.S.The multifaceted roles of glycogen synthasese kinase-3beta in cellular singaling.Prog.Neurobiol.2001,65:391-426.
[21] Van Antwerp J.D.,mMartin J.S.,Kafri T.,Green D.R.and Verma I.M. (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB.Science. 1996, 274:787-789
[22] Demarchi F.,Bertolo C.,Sandyy P. and Schneider C.Glycogen synthase kinase-3 beta regulates NF-kappa BI/P105 stability.J.Biol.chem.2003,278:39583-39590.
[23] Deng J.,Xia w .,Miller A.s,Wen y,wang H.Y.and Hung M.C. Crossregulation of NF-kappaB by the APC/GSK-3beta/beta-catenin pathway.Mol.Carcinog. 2004, 39:139-146.
[24] De strooper B.and Annaert W.Where Notch and Wnt signaling meet:the presenilin hub J.Cell Biol.2001,152:F17-G20.
[25] Anderton H.B,Dayanadan R.,kellick R.and Lovestone S.Does dysregulation of the Notch and wingless/Wnt pathways underline the pathogensis of Alzheimer's disease? Mol.Med.Today 2000,6:54-59.
[26] Ignacio Mateo,Jon Infante,Javier Liorca et al.Association between Glysogen synthase kinase-36 Genetic polymorphism and Late-onset Alzheimer's Disease Dement Geriatr Cogn Disord 2006.21:228-232.
[1]Kyriakis JM,Avruch J.Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation[J].Physiol Rev,2001,81(2):807-869.
[2]Adachi T,Kar S,WangM,et al.Transient and sustained ERK phosphorylation and nuclear translocation in growth control.J Cell Physiol,2002,192(2):1512159.
[3]Swatton JE,Sellers LA,Faull RL,et al.Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain2004May;19(10):2711-9.
[4]Zhu X,Rottkamp CA,Boux H et al.Activation of p38 kinase links tau phosphorylation,oxidative stress,and cell cycle2related events in Alzheimer disease.J Neuropathol Exp Neurol,2000;59(10):880-8
[5]Hyman BT,Elvhage TE,Reiter J.Extracellular signal regula2 ted kinases.Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease.Am J Pathol,1994,144(3):565 25 7 2.
[6]罗友根,周新文等,同型半胱氨酸对tau蛋白磷酸化的影响及机制探讨.山东医药,2006 Vol.46 No.36 P.25-26
[7]Savage MJ,Lin YG,Ciallella JR,et al.Activation of c 2Jun N 2terminal kinases and p38 in an Alzheimer's Disease Model is Assocated with Amyloid Deposition.J Neurosci,2002,22
[8]Veeranna,Kaji T,Boland B,et al.Calpain Mediates Calci2 um 2Induced Activation of the Erk1,2 MAPK Pathway and Cy2toskeletal Phosphorylation in Neurons Relevance to Alzheimer's Disease.Am J Pathol,2004,165(3):795 28 0 5.
[9]Pei JJ,Gong CX,An WL,et al.Okadaic 2acid 2induced inhi2 bition of protein phosphatase 2A produces activation of mitogen 2 activated protein kinases ERK1/2,MEK1/2,and p70S6,similar to that in Alzheimer's disease.Am.J.Pathol,2003,163(3):845 28 5 8.
[10] Swatton JE, SellersLA, FaullRL, et al. IncreasedMAP kinase ac2 tivity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci, 2004,19 (10) : 271122719.
[11] SunA, LiuM, NguyenXV, et al. P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp Neurol, 2003,183 (2): 3942405.
[12] Oo TF, Henchcliffe C , James D , et al. Expression of c -fos , c -jun , and c -jun N -terminal kinase (JNK) in a developmental model of in2 duced apoptotic death in neurons of the substantia nigra. J Neurochem , 1999, 72 (2) : 557 -564.
[13] Yang DD , Kuan CY, Whitmarsh AJ , et al. Absense of excitotoxicity -induced apoptosis in the hippocampus of mice lacking the JNK3 gene. Nature , 1997 , 389 (6653): 865 -870.
[14] Luo Y, Umegaki H, Wang X, et al. Dopamine induces apoptosis through an oxidation -involved SAPK/ JNK activation pathway. JBC , 1998 , 273 (6): 3756 -3764.
[15] Fernande A,Falcao AS,Silva RF,et al MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes. 2007 Feb;25(4):1058-68.
[16] XU Z,Wang BR,Wang X et al ERKl/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury. 2006 Oct 12;79(20):1895-905. Epub 2006 Jun 21.
[17] Shoji M,lwakeuchi S,et al.JNK activated is associated with intrasellular beta-amyloid accumulation.Brain Res Mol Brain Res,2000,85(1-2):221-233.
[18] Yao M, Nguyen TV, Pike CJ. Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. 2005 Feb 2;25(5):1149-58.
[19] Hensley K , Floyd RA , Zheng N Y et al. p38 kinase is activated in the Alzheimer's disease brain. J Neurochem , 1999 ;72 (5) :2053 ～8
[20] McDonald DR, Bamberger ME, Combs CK, et al. Beta2 Amyloid fibrils activate parallel mitogen2activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci, 1998 ;18 (12) :4451～60
[21] Yao M,Nguyen TV,Pike CJ.Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death. 2007 Feb 7;27(6): 1422-33.
[22] Sweat J D,Mitogen-activated protein kinase in synaptic plasticity and memory[J].Cerr Opin Neurobol,2004,14(3):311-7
[23] Wu G Y,Deisseroth K,Tsien R W.spaced stimuli stabilize MAPK pathway activation and its effects on dendritec morphology [J].Nat Neurosci,2001,4(2):15
[2]何燕.中药多糖的免疫调节作用[J].四川中医,2001,19(2):15-17.
[3]BayerTA,Wirths O,Majtenyik,etal.Key factors in Alzhermer's diseases:beta-amyloid precursor protein processing,metabolism and traneuronaltransport.Brain Pathol 2003;11(1):1-4.
[4]John H.M.& Patrick R.H.Life death of neurons in the aging brain.Science 2003,278(9):412-416.
[5]Maccioni B.R,Munoz P.J.&Barbeito L.The molecular bases of Alzheimer's disease and other neurodegenerative disases.Archives of Medical Research 2002;32(6):81.
[6]Henderson V.W.,et al.The neurobiology of Alzheimer's desease.J Neurosur 1998;70(12):335-337.
[7]郭文平,付欣鸽,倪振贤.Aβ25-35对培养大鼠大脑皮质和海马神经元存活和生长的影响[J].农垦医学,1999,21(4):242.
[8]Bayer TA,Wirths O,Majtenyik,etal.Key factors in Alzheimer's disease:betaamyloid precursor protein processing,metabolism and intraneuronaltransport.Brain Pathol 2003;11(1):1-5.
[9]Grimes C A,Jope R S.The multifaceted roles of glycogen Requirement for synthase kinase 3b in cellular signaling.Prog Neurobiol,2001,65:391-426.
[10 Woodgett J R.Judging a protein by more than its name:GSK-3.Sci STKE,2001,100:RE12.
[11]Woodgett J R.Molecular cloning and expression of glycogensynthase kinase-3/factor A.EMBO J,1990,9:2431-2438.
[12]Flaherty B.D,Soria P.J,Tomasiewicz H.G et al Phosphotylation of human tau protein by microtubule-associated kinases:Gsk-3beta and cdk5 are key participants.J.Neurosi.62:463-472.
[13]Fath T,Eidenmuller J.and Brandt R.Tau-mediated cytotoxicity in pseudohyperphosphotylation model of Alzheimer's disease.J.neurosci.22:9733-9741.
[14]Ilouz R,Kowalsman N,Eisenstein M.Identification of novel glycogen synthase kinase-3beta substrate-interacting residues suggests a common mechanism for substrate recognition.J Biol Chem.2006 Oct 13;281(41):30621-30.
[15]江刚,舒斯云,包新民。CREB与中枢学习记忆功能的关系[J]。中国临床康复,2004,8(1):124-6.
[16]Lonze BE,Glnty DD,Function and regulation of CREB family transcription faors in the nervous system.Neuron 2002;35(4):605-3.
[17]Meng Y,Xu H,Wang R,et al.Impainment of singal transduction pathway on neuronal survival in brains of Alzheimers disease[J].zhonghua bing Li Xue Za Zhi,2002,31:502-5.
[18]Liang Z,Liu F,Grundke-Iqbal I,Down-regulation of cAMP-dependent protein kinase in Alzheimer disease brain.J Neurochem.2005 Dec;103(6):2462-70.Epub 2007 Oct 1.
[19]包新民,舒斯云.大鼠脑立体定位图谱.北京:人民卫生出版社,1991.44.
[20]Selkoe JD.Amyloid protein and Alzheimer's disease[J].Scientific American,1991,265(5):68.
[21]Masters CL,Simms G.Weinman NA,et al.Amyloid plaque core protein in Alzheimer's disease and down syndrome[J].Proc Natl Acad Sci USA,1985,82:4245.
[22]Mullan M.Crawford F.Genetic and molecular advances in Alzheimer's disease[J].Trends Neurosci,1993,16:398.
[23]Cotton P.Constellation of risks and processes seen in search for Alzheimer's disease[J].JAMA,1994,271(2):89.
[24]Cosgays JM,Latasa MJ,Pascua IA.Nerve growth factor and ras regulate beta-amyloid precusor protein gene expression in PC12 cells[J].J Neurochem,1996,67(1):98.
[25]Dvis K L,Thal L J,Garmzu ER,et al.A double-blind,placebo-controlled multicenter study of tacrine for Alzheimer's disease[J].New Engl J Med,1992,327(8):1253.
[26]胡桃英.论痴呆与痰凝血淤的关系.湖南中医药导报.1997,3(2):8-9.
[27]李海涛,曾莉.祖国医学对老年痴呆症的认识与研究.中医药学刊,2004,3:12-14
[W]胡桃英.论痴呆与痰凝血淤的关系.湖南中医药导报.1997,3(2):8-9.
[28]郭苏云,张映梅.补肾益脑为主治疗老年性痴呆.云南中医学院学报.2003,26(1):40-41.
[29]刘辉,陈俊抛,田时雨,等.Aβ1-40海马注射对大鼠脑内一氧化氮合酶表达的影响.中华神经科杂志[J],2001,34(2):92-95.
[30]Giovannelli L,Casamenti F,Scali C,et al.Differential effects of amyloid peptides beta-(1-40)and beta-(25-35)injections into the rat nucleus basalis.Neuroscience.1995,66(4):781-792.
[31]刘辉,陈俊抛,田时雨,等.海马注射β淀粉样蛋白对大鼠学习记忆及局部神经元的损伤作用.中华神经科杂志[J],2000,33(3):150-152.
[32]许士凯.抗衰老药物学.北京:中国医药科技出版社,1994.219-285.
[33]柯尊记,姚志杉.空间学习记忆的行为模式及其分子神经生物学基础[J].解剖科学进展,1998,4(1):1-7.
[34]Morris R GM.Developments of a water maze procedure for studying,spatial learning in the rat[J].J Neruo Sci Meth,1984,11:47.
[35]Delacourte A,Buee L.Tau pathology:neurodegenerative disorders.Curr.Op in.Neuro,2002,13,3712-3761.
[36]NielsA,Camilla H,Pia D,etal.Cerebrospianl fluidβ-Amyloid(1-42)in Alzheimerdisease[J].Arch Neurol,1999,56:673-680.
[37]王德生,张守信.老年性痴呆.北京:人民卫生出版社,2002:28-32.
[38]Bayer TA,Wirths O,Majtenyik,etal.Key factors in Alzhermer's diseases:betaamyloid precursor protein processing,metabolism traneuronal transport.Brain Pathol 2003;11(1):1.
[39]John H.M.& Patrick R.H.Life death of neurons in the aging brain.Science 2003;278(9):412-416.
[40]Flaherty B.D,Soria P.J,Tomasiewicz H.G et al Phosphotylation of human tau protein by microtubule-associated kinases:Gsk-3beta and cdk5 are key participants.J.Neurosi.62:463-472.
[41]Fath T,Eidenmuller J.and Brandt R.Tau-mediated cytotoxicity in pseudohyperphosphotylation model of Alzheimer's disease.J.neurosci.22:9733-9741.
[42]Hansen TO,Rehfeld JF,Nielsen FC.GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding.Neuroreport.2004Apr 9;15(5):841-5.
[43]CREB DNA binding activity is inhibited by glycogen synthase kinase-3β and facilitated by lithium.J Neurochem.2001 September;78(6):1219-1232.
[44]Leutgeb J K,Frey J U,Behnisch T.Single cell analysis of activity-dependent cyclic AMP-responsive element-binding protein phosphrylation long-lasting long-term potentiation in area CA1.
[45]Sambamurti K,Kinsey R,Maloney B,et al.Gene structure and organization of the human beta-seceretase(BACE)promoter[J].FASEB J,2004,18:1.34-6.
[46]Meng Y,Xu H,Wang R,et al.Impairment of signal transduction pathway on neuronal survival in brains of Alzheimers disease[J].zhonghua Bing Li Xue Za zhi,2002,31:5.2-5.
[47]傅仁杰.老年呆病的诊断、辨证分型及疗效评定标准(讨论稿)[J].中医杂志,1991,32(1):56.
[48]李海涛,曾莉.祖国医学对老年痴呆症的认识与研究[J].中医药学刊,2004,3:121.
[49]徐江平,杨雪梅。中草药活性成分防治阿尔采末病的研究进展[J]。第一军医大学学报,2001,1:23-26.
[50]张丹参,张均田。人参皂苷对大鼠海马齿状回突传递活动的影响[J]。药学学报,2000,35(3):185-188.
[51]陈晓光,崔志勇,等.何首乌对老年小鼠衰老指标的影响[J].中草药,191,22(8):359.
[52]Y angZ H.R ecentre searchs ituationo fan ti-agingr eactiono f Po lyg on um m ultiflorum Thunb.[J].L ishixhenM edM ater Me d R e s(时珍国医国药),1999,10(5):3 90-391.
[53]杨永昌.藏药志[M],西宁:青海人民出版社,1991:34.
[54]姜文华,王淑兰,关桂梅,红景天素对大鼠中枢神经系统的抗衰老作用的实验研究[J],白求恩医科大学学报,1959,21(1):8.
[55]zhang ZJ,Jiang W,Wan Q.Effect of rhodiola on lipidpenroxides and ultrastructure of mitochondria in the brain of senile mice[J].chin J clin Rehabil,2005;9(9):235-7.
[56]钱彦丛,秦葵,刘景东.红景天的化学及药理研究[J].北京军区医药,199;6(11):452-4.
[57]黄兆胜。中药对老年性痴呆中枢神经系统作用研究进展。[J]广州中医药大学学报,2000,(2):21-24.
[58]王月芳,万海同。论肾虚痰凝血瘀是老年性痴呆的重要发病机制[J]。中国中医基础杂志,2001,5(8):9-10.
[59]刘运林,何明大,周泽.脑灵汤对阿尔茨海默病血脂血流变的影响[J].中国血液流变学杂志.2006;16(1):69-71.
[60]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.
[61]Cotman CW,Tenner AJ,Cummings BJ.Beta-Amyloid converts anacute phase injury response to chronic injury responses.Neurobiol Aging,1996,17:723-731.
[62]何明大,刘运林。脑灵汤对阿尔茨海默病模型鼠凋亡调控基因的影响。中国现代医学杂志,2005,15(22)3398-3401.
[63]谭赛辉,杨建钢。脑灵汤对阿尔茨海默病模型大鼠海马CA3区域GFAP和IL-1β表达的影响,待发表.
[64]Delacourte A,Buee L.Tau pathology:neurodegenerative disorders.Curr.Opin.Neuro,2002,13,371-376.
[1]Cleveland DW,Hwo SY,Kirschner MW.Physical and chem-ical properties of purified tau factor and the role of tau in micro-tubule assembly.J Mol Biol,1977,116:227.
[2]Biernat J,Gustke N,Drewes G,et al.Phosphorylation of Ser262strongly reduces binding of tau to microtubules:distinc-tion between PHF-like immunoreactivity and microtubulebind-ing.Neuron,1993,11:153.
[3]Arend T.Neurogeneration and plasticity.INT.J.Dev.Neurosci.2004,22:9733-9741.
[4]Blennow K,Vanmechelen E,Hampel H.CSF total tau,Abe-ta42 and phosphorylated tau protein as biomarkers forAlzheimer's disease.Mol Neurobiol,2001,24(1-3):87.
[5]Ishiguro K,Omori A,Takamastsu M,et al.Phosphorylation sites on tau by tau protein kinase 1,a bovine derived kinase generating an epitope of paired helical filaments.Nuerosci.Lett.148:202-206.
[6]Lucas J.J,Hemandez E,Gomez-Ramos P.,et al.Decreased nuclear beta-catenin R,tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice.EMBOJ.2001,20:27-39.
[7]周洁,陈娟,肖志宏等。载断型载脂蛋白E4对培养神经元细胞中神经细丝磷酸化的影响。[J]。中国临床康复。2006,10(46):209-211.
[8]Kim S.H.,Kim M.E.,Lee p.J.,et al.C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glyloid synthase kinase-3beta expression.FASEB J.2005,17:1951-1953.
[9]Gao Y.and Pimplikar S.W.The gamma-secretase-cleaved C-terminal framment of amyloid precursor protein mediates sinaling to the nucleus.Pros Natl.Acad.sci.USA 2001,98:14979-14984.
[10]Ryan K.A and pimplikar S.W.Activatiom of GSK-3 and phosphorylation of CRMP-2 in transgenic mice expressing APP intracellular domain.J,cell.Biol.2005,171:327-335.
[11] Su Y.,Ryder J.,LiB.,wu x.et al. Lithium,a commom drug for bipolar "disorder treatment,regulates amyloid-beta precursor protein processing,Biochemistry 2004,43:6899-6908.
[12] E.H.Karran,D.Allsop,GChristie,et al.Presenilins in searth of functionally. Biochemical societu Transactions,1992,23(3):491-496.
[13] Weihl,Ye Y.Ghadge D.G,Kennedy Gs .Mutant presenilin-1 induces apoptosis and downregulates AKT/PKB.J Neurosci.l999,19:5360-5369.
[14] Baki L,shioi J,Shao Z,Schwarxman A,et al.(2004)PSl activates PI3K thus inhibiting GSK-3 activity and Tau overphosphorylation:effects of FAD mutations. EMBO J.2004,23:2586-2596.
[15] Takachima A,Murayama M,Murayama.et al.(1998)presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.Proc.Natl.Acad. Sci.USA.1998,23:9637-9641.
[16] Pigna G,Morfini G,pelsman A,Mattson P.M and Busciglio J.Alzheimer's presenilin 1 mutations impair kinase based axonal transport.J.Neurosci. 2003, 23:4499-4508.
[17] Kirschenbaum F,Hsu c.s,Cordell B and McCarthy J.V. Substitution of a glycogen synthase kinase-3 beta phosphorylation site in the presenlin 1 seperates presenilin function from beta-catenin signaling .J.Biol.chen.2001,276:7366- 7375.
[18] Kirschenbaum F.,Hsu c s ,cordell B,and MdCarthy J.V.Glycogen synthase kinase-3 beta regulaes presenilin 1 c-terminal fragment levels.J.Biol.chem. 2001, 276:30701-30707.
[19] Pap M.and Cooper GM.Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival patyway.J.Biol.chem. 1998,273: 19929-19932.
[20] Grimes C.A.and Jope R.S.The multifaceted roles of glycogen synthasese kinase-3beta in cellular singaling.Prog.Neurobiol.2001,65:391-426.
[21] Van Antwerp J.D.,mMartin J.S.,Kafri T.,Green D.R.and Verma I.M. (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB.Science. 1996, 274:787-789
[22] Demarchi F.,Bertolo C.,Sandyy P. and Schneider C.Glycogen synthase kinase-3 beta regulates NF-kappa BI/P105 stability.J.Biol.chem.2003,278:39583-39590.
[23] Deng J.,Xia w .,Miller A.s,Wen y,wang H.Y.and Hung M.C. Crossregulation of NF-kappaB by the APC/GSK-3beta/beta-catenin pathway.Mol.Carcinog. 2004, 39:139-146.
[24] De strooper B.and Annaert W.Where Notch and Wnt signaling meet:the presenilin hub J.Cell Biol.2001,152:F17-G20.
[25] Anderton H.B,Dayanadan R.,kellick R.and Lovestone S.Does dysregulation of the Notch and wingless/Wnt pathways underline the pathogensis of Alzheimer's disease? Mol.Med.Today 2000,6:54-59.
[26] Ignacio Mateo,Jon Infante,Javier Liorca et al.Association between Glysogen synthase kinase-36 Genetic polymorphism and Late-onset Alzheimer's Disease Dement Geriatr Cogn Disord 2006.21:228-232.
[1]Kyriakis JM,Avruch J.Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation[J].Physiol Rev,2001,81(2):807-869.
[2]Adachi T,Kar S,WangM,et al.Transient and sustained ERK phosphorylation and nuclear translocation in growth control.J Cell Physiol,2002,192(2):1512159.
[3]Swatton JE,Sellers LA,Faull RL,et al.Increased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain2004May;19(10):2711-9.
[4]Zhu X,Rottkamp CA,Boux H et al.Activation of p38 kinase links tau phosphorylation,oxidative stress,and cell cycle2related events in Alzheimer disease.J Neuropathol Exp Neurol,2000;59(10):880-8
[5]Hyman BT,Elvhage TE,Reiter J.Extracellular signal regula2 ted kinases.Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease.Am J Pathol,1994,144(3):565 25 7 2.
[6]罗友根,周新文等,同型半胱氨酸对tau蛋白磷酸化的影响及机制探讨.山东医药,2006 Vol.46 No.36 P.25-26
[7]Savage MJ,Lin YG,Ciallella JR,et al.Activation of c 2Jun N 2terminal kinases and p38 in an Alzheimer's Disease Model is Assocated with Amyloid Deposition.J Neurosci,2002,22
[8]Veeranna,Kaji T,Boland B,et al.Calpain Mediates Calci2 um 2Induced Activation of the Erk1,2 MAPK Pathway and Cy2toskeletal Phosphorylation in Neurons Relevance to Alzheimer's Disease.Am J Pathol,2004,165(3):795 28 0 5.
[9]Pei JJ,Gong CX,An WL,et al.Okadaic 2acid 2induced inhi2 bition of protein phosphatase 2A produces activation of mitogen 2 activated protein kinases ERK1/2,MEK1/2,and p70S6,similar to that in Alzheimer's disease.Am.J.Pathol,2003,163(3):845 28 5 8.
[10] Swatton JE, SellersLA, FaullRL, et al. IncreasedMAP kinase ac2 tivity in Alzheimer's and Down syndrome but not in schizophrenia human brain. Eur J Neurosci, 2004,19 (10) : 271122719.
[11] SunA, LiuM, NguyenXV, et al. P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp Neurol, 2003,183 (2): 3942405.
[12] Oo TF, Henchcliffe C , James D , et al. Expression of c -fos , c -jun , and c -jun N -terminal kinase (JNK) in a developmental model of in2 duced apoptotic death in neurons of the substantia nigra. J Neurochem , 1999, 72 (2) : 557 -564.
[13] Yang DD , Kuan CY, Whitmarsh AJ , et al. Absense of excitotoxicity -induced apoptosis in the hippocampus of mice lacking the JNK3 gene. Nature , 1997 , 389 (6653): 865 -870.
[14] Luo Y, Umegaki H, Wang X, et al. Dopamine induces apoptosis through an oxidation -involved SAPK/ JNK activation pathway. JBC , 1998 , 273 (6): 3756 -3764.
[15] Fernande A,Falcao AS,Silva RF,et al MAPKs are key players in mediating cytokine release and cell death induced by unconjugated bilirubin in cultured rat cortical astrocytes. 2007 Feb;25(4):1058-68.
[16] XU Z,Wang BR,Wang X et al ERKl/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury. 2006 Oct 12;79(20):1895-905. Epub 2006 Jun 21.
[17] Shoji M,lwakeuchi S,et al.JNK activated is associated with intrasellular beta-amyloid accumulation.Brain Res Mol Brain Res,2000,85(1-2):221-233.
[18] Yao M, Nguyen TV, Pike CJ. Beta-amyloid-induced neuronal apoptosis involves c-Jun N-terminal kinase-dependent downregulation of Bcl-w. 2005 Feb 2;25(5):1149-58.
[19] Hensley K , Floyd RA , Zheng N Y et al. p38 kinase is activated in the Alzheimer's disease brain. J Neurochem , 1999 ;72 (5) :2053 ～8
[20] McDonald DR, Bamberger ME, Combs CK, et al. Beta2 Amyloid fibrils activate parallel mitogen2activated protein kinase pathways in microglia and THP1 monocytes. J Neurosci, 1998 ;18 (12) :4451～60
[21] Yao M,Nguyen TV,Pike CJ.Estrogen regulates Bcl-w and Bim expression: role in protection against beta-amyloid peptide-induced neuronal death. 2007 Feb 7;27(6): 1422-33.
[22] Sweat J D,Mitogen-activated protein kinase in synaptic plasticity and memory[J].Cerr Opin Neurobol,2004,14(3):311-7
[23] Wu G Y,Deisseroth K,Tsien R W.spaced stimuli stabilize MAPK pathway activation and its effects on dendritec morphology [J].Nat Neurosci,2001,4(2):15