人参皂苷Rd对阿尔茨海默病模型的神经保护作用及机制探讨
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摘要
阿尔茨海默病(Alzheimer disease, AD)多在老年时期起病，起病隐秘，病程缓慢时间长且不可逆，是一组目前病因并不明确的脑部原发性退行性变性疾病。临床上以学习记忆认知能力进行性衰退为主，常伴有一定程度的语言、精神和人格等方面的异常。而其基本病理特点表现为Aβ沉积形成的老年斑、磷酸化Tau蛋白沉积形成的神经纤维缠结以及大量胆碱能神经元的丢失等。由于AD病人发病影响因素较多，病因病理机制非常复杂，故目前治疗并无明显突破，缺乏有效安全的治疗药物与手段。
课题组人员前期已经发现人参皂苷Rd能够抑制AD模型鼠海马内炎症反应的发生，抑制培养的海马神经元氧化应激损伤而保护神经元。故本课题以此为研究基础，从体内、体外、纯体外三方面观察Rd对实验性AD模型的神经保护作用并对其机制作初步探讨，为开发安全有效的防治AD新药提供基础研究依据。
研究目的：探讨人参皂苷Rd对实验性AD模型的学习记忆、病理特征的影响及对其保护机制的初步探讨，为寻找防治AD药物以及研究Rd作用靶点提供一定的实验基础。
研究方法：（1）研究对象：急性脑损伤模型：成年清洁级SD大鼠双侧海马CA1区立体定向微量注射Aβ1-40；慢性AD动物模型：APP转基因小鼠；体外细胞模型：Aβ25-35干预的皮层神经元。（2）对急性脑损伤模型大鼠和APP转基因小鼠进行Morris水迷宫检测观察Rd对AD模型动物的学习记忆行为能力的影响，Nissl染色观察其组织形态学变化；对Aβ25-35干预的皮层神经元进行MTT染色观察Rd对其存活率的影响和进行免疫荧光染色观察细胞形态学变化。（3）Western blot方法检测磷酸化Tau蛋白主要磷酸化位点的表达，观察Rd对AD模型内病理特征的影响，同时对调控磷酸化Tau蛋白的关键激酶和磷酸酶的表达也进行了观察。初步探讨Rd对AD模型动物的保护作用机制。（4）体外纯化学实验进一步排除各种体内体外环境的影响，Western blot方法检测化学反应后磷酸化Tau蛋白主要磷酸化位点表达的变化，进一步探讨Rd对AD模型动物的保护的作用机制及其作用靶点。
实验结果：（1）Rd（5，10，30mg/kg）对Aβ1-40急性脑损伤大鼠的学习记忆功能均有改善:能够缩短海马微量注射Aβ1-40大鼠水迷宫逃避潜伏期的时间、增加模型鼠穿越原平台次数，减少模型鼠海马CA1区神经元的丢失；Rd（10mg/kg）可明显改善APP转基因小鼠的学习记忆功能：缩短APP转基因小鼠水迷宫逃避潜伏期的时间、增加模型鼠穿越原平台次数；Rd（2.5，5μM）能提高体外培养皮层神经元的活性；（2）Rd能够减少各模型组磷酸化Tau蛋白的表达，抑制GSK-3β的表达，提高PP-2A的活性；（3）体外纯化学实验结果表明Rd能够减少化学反应后各磷酸化位点Tau蛋白的表达。
实验结论：人参皂苷Rd增强了实验性AD模型动物的学习记忆能力，提高了AD细胞模型的存活率。其机制可能为Rd能抑制GSK-3β的表达与活性，提高PP-2A的活性，从而减少过度磷酸化Tau蛋白的形成与沉积，发挥其对AD模型的神经保护作用。
Alzheimer's disease, a central, primary, progressive and degenerative disease,is a relatively common form of senile dementia patients. Its clinical performanceis the cognitive disabilities, learning and memory recession, often accompaniedby exception of the language, spirit and personality. While its basic pathology ischaracterized by the senile plaques formed by Aβ deposition, neurofibrillarytangles formed by phosphorylated Tau protein deposition as well as a largenumber of cholinergic neurons lost. The incidence of AD patients is affected bymany factors and etiology and pathological mechanism is very complex.Therefore, nowadays the treatment of AD has no significant breakthroughs andthe effective and safe therapy and means are lacking.
Our research group has found that ginsenoside Rd could inhibit theinflammatory response in hippocampus of AD rat model, inhibit oxidative stressdamage in cultured hippocampal neurons and protect neurons. Based on thoseresults, we observed neuroprotective effect of Rd on the experimental model ofAD and its mechanism from three aspects: in vitro, in vivo and pure in vitro chemical experiments. It can provide a basis for the development of safe andeffective prevention and a new drug of treatment of AD.
Objective: To study protective effects of learning and memory in theexperimental models of AD, impact of Rd on pathological features and theirmechanisms of neuroprotection, it provide some experimental basis to search forthe protective drug of AD.
Methods:(1) Objects of study: acute brain injury model: SD rats with bilateralhippocampal CA1region of stereotactic micro-injection of Aβ1-40; chronic ADanimal model: APP transgenic mice; cell model in vitro: cortical neurons treatedby Aβ25-35.(2) Morris water maze was used to observe the effects of Rd onlearning and memory capacity in the rats of model about acute brain injury andAPP transgenic mice, and nissl staining was used to observe histological changes.MTT method was used to observe the survival of Aβ25-35treated cortical neuronsand immunofluorescence staining were used to observe the morphologicalchanges.(3) Western blot was used to detect the expression of phosphorylatedTau protein and the expression of kinase and phosphatase regulatingphosphorylated Tau protein was also observed. Those results discussed theprotective mechanisms of Rd in animal models of AD.(4) to further rule out thevarious environmental impacts in vitro and in vivo, pure chemical experiments invitro were used to detect the expression changes of phosphorylated Tau proteinby Western blot method after chemical reactions. It further explored theprotection mechanism of Rd in animal models of AD and the target of Rd.
Results:(1) Rd (5,10,30mg/kg) on learning and memory functions in Aβ1-40induced rats showed some improvements: the time of escape latency wasshortened in Aβ1-40induced rats, the number of crossing over the originalplatform was increased, and the loss of hippocampal CA1neurons of rat model was reduced; Rd (10mg/kg) could significantly improve learning and memory inAPP transgenic mice: Shortened the time of escape latency and increased thenumber of crossing over the original platform; Rd (2.5,5μM) could improve thesurvival of cultured cortical neurons;(2) Rd was able to reduce the expression ofphosphorylated Tau protein, inhibit expression of GSK-3β and improve thePP-2A activity;(3) Pure chemistry experiment results showed that Rd was able toreduce the phosphorylated Tau protein after chemical reaction.
Conclusion: Rd could enhance the abilities of learning and memory inexperimental AD animal models and the survival rate of the cellular model of AD.The mechanism of Rd may be related to inhibiting GSK-3β expression andactivity of PP-2A. Therefore Rd could reduce the formation and deposition ofexcessive phosphorylation of Tau protein and play a neuroprotective effect on theAD model.
课题组人员前期已经发现人参皂苷Rd能够抑制AD模型鼠海马内炎症反应的发生，抑制培养的海马神经元氧化应激损伤而保护神经元。故本课题以此为研究基础，从体内、体外、纯体外三方面观察Rd对实验性AD模型的神经保护作用并对其机制作初步探讨，为开发安全有效的防治AD新药提供基础研究依据。
研究目的：探讨人参皂苷Rd对实验性AD模型的学习记忆、病理特征的影响及对其保护机制的初步探讨，为寻找防治AD药物以及研究Rd作用靶点提供一定的实验基础。
研究方法：（1）研究对象：急性脑损伤模型：成年清洁级SD大鼠双侧海马CA1区立体定向微量注射Aβ1-40；慢性AD动物模型：APP转基因小鼠；体外细胞模型：Aβ25-35干预的皮层神经元。（2）对急性脑损伤模型大鼠和APP转基因小鼠进行Morris水迷宫检测观察Rd对AD模型动物的学习记忆行为能力的影响，Nissl染色观察其组织形态学变化；对Aβ25-35干预的皮层神经元进行MTT染色观察Rd对其存活率的影响和进行免疫荧光染色观察细胞形态学变化。（3）Western blot方法检测磷酸化Tau蛋白主要磷酸化位点的表达，观察Rd对AD模型内病理特征的影响，同时对调控磷酸化Tau蛋白的关键激酶和磷酸酶的表达也进行了观察。初步探讨Rd对AD模型动物的保护作用机制。（4）体外纯化学实验进一步排除各种体内体外环境的影响，Western blot方法检测化学反应后磷酸化Tau蛋白主要磷酸化位点表达的变化，进一步探讨Rd对AD模型动物的保护的作用机制及其作用靶点。
实验结果：（1）Rd（5，10，30mg/kg）对Aβ1-40急性脑损伤大鼠的学习记忆功能均有改善:能够缩短海马微量注射Aβ1-40大鼠水迷宫逃避潜伏期的时间、增加模型鼠穿越原平台次数，减少模型鼠海马CA1区神经元的丢失；Rd（10mg/kg）可明显改善APP转基因小鼠的学习记忆功能：缩短APP转基因小鼠水迷宫逃避潜伏期的时间、增加模型鼠穿越原平台次数；Rd（2.5，5μM）能提高体外培养皮层神经元的活性；（2）Rd能够减少各模型组磷酸化Tau蛋白的表达，抑制GSK-3β的表达，提高PP-2A的活性；（3）体外纯化学实验结果表明Rd能够减少化学反应后各磷酸化位点Tau蛋白的表达。
实验结论：人参皂苷Rd增强了实验性AD模型动物的学习记忆能力，提高了AD细胞模型的存活率。其机制可能为Rd能抑制GSK-3β的表达与活性，提高PP-2A的活性，从而减少过度磷酸化Tau蛋白的形成与沉积，发挥其对AD模型的神经保护作用。
Alzheimer's disease, a central, primary, progressive and degenerative disease,is a relatively common form of senile dementia patients. Its clinical performanceis the cognitive disabilities, learning and memory recession, often accompaniedby exception of the language, spirit and personality. While its basic pathology ischaracterized by the senile plaques formed by Aβ deposition, neurofibrillarytangles formed by phosphorylated Tau protein deposition as well as a largenumber of cholinergic neurons lost. The incidence of AD patients is affected bymany factors and etiology and pathological mechanism is very complex.Therefore, nowadays the treatment of AD has no significant breakthroughs andthe effective and safe therapy and means are lacking.
Our research group has found that ginsenoside Rd could inhibit theinflammatory response in hippocampus of AD rat model, inhibit oxidative stressdamage in cultured hippocampal neurons and protect neurons. Based on thoseresults, we observed neuroprotective effect of Rd on the experimental model ofAD and its mechanism from three aspects: in vitro, in vivo and pure in vitro chemical experiments. It can provide a basis for the development of safe andeffective prevention and a new drug of treatment of AD.
Objective: To study protective effects of learning and memory in theexperimental models of AD, impact of Rd on pathological features and theirmechanisms of neuroprotection, it provide some experimental basis to search forthe protective drug of AD.
Methods:(1) Objects of study: acute brain injury model: SD rats with bilateralhippocampal CA1region of stereotactic micro-injection of Aβ1-40; chronic ADanimal model: APP transgenic mice; cell model in vitro: cortical neurons treatedby Aβ25-35.(2) Morris water maze was used to observe the effects of Rd onlearning and memory capacity in the rats of model about acute brain injury andAPP transgenic mice, and nissl staining was used to observe histological changes.MTT method was used to observe the survival of Aβ25-35treated cortical neuronsand immunofluorescence staining were used to observe the morphologicalchanges.(3) Western blot was used to detect the expression of phosphorylatedTau protein and the expression of kinase and phosphatase regulatingphosphorylated Tau protein was also observed. Those results discussed theprotective mechanisms of Rd in animal models of AD.(4) to further rule out thevarious environmental impacts in vitro and in vivo, pure chemical experiments invitro were used to detect the expression changes of phosphorylated Tau proteinby Western blot method after chemical reactions. It further explored theprotection mechanism of Rd in animal models of AD and the target of Rd.
Results:(1) Rd (5,10,30mg/kg) on learning and memory functions in Aβ1-40induced rats showed some improvements: the time of escape latency wasshortened in Aβ1-40induced rats, the number of crossing over the originalplatform was increased, and the loss of hippocampal CA1neurons of rat model was reduced; Rd (10mg/kg) could significantly improve learning and memory inAPP transgenic mice: Shortened the time of escape latency and increased thenumber of crossing over the original platform; Rd (2.5,5μM) could improve thesurvival of cultured cortical neurons;(2) Rd was able to reduce the expression ofphosphorylated Tau protein, inhibit expression of GSK-3β and improve thePP-2A activity;(3) Pure chemistry experiment results showed that Rd was able toreduce the phosphorylated Tau protein after chemical reaction.
Conclusion: Rd could enhance the abilities of learning and memory inexperimental AD animal models and the survival rate of the cellular model of AD.The mechanism of Rd may be related to inhibiting GSK-3β expression andactivity of PP-2A. Therefore Rd could reduce the formation and deposition ofexcessive phosphorylation of Tau protein and play a neuroprotective effect on theAD model.
引文
[1] Xiaochun Chen, Tianwen Huang, Jing Zhang, Jinqiu Song, Limin Chen,Yuangui Zhu. Involvement of calpain and p25of CDK5pathway inginsenoside Rb1's attenuation of β-amyloid peptide25–35-induced tauhyperphosphorylation in cortical neurons. Brain Research,1200,2008:99-106.
[2] Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL,Beyreuther K. Amyloid plaque core protein in Alzheimer disease andDown syndrome. Proc Natl Acad Sci USA,1985,82:4245-9.
[3] Miller DL, Papayannopoulos IA, Styles J, Bobin SA, Lin YY, Biemann K,Iqbal K. Peptide compositions of the cerebrovascular and senile plaquecore amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys,1993,301:41-52.
[4] Iqbal K, Wisniewski HM, Shelanski ML, Brostoff S, Liwnicz BL, TerryRD. Protein changes in senile dementia. Brain Res,1974,77:337-43.
[5] Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, WisniewskiHM. Microtubule-associated protein tau. A component of Alzheimer pairedhelical filaments. J. Biol. Chem.,1986,261:6084-9.
[6] Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, BinderLI. Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA.,1986,83:4913-7.
[7] Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS,Wisniewski HM, Alafuzoff I, Winblad B. Defective brain microtubuleassembly in Alzheimer’s disease. Lancet,1986,2:421-6.
[8] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356.
[9] Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer'sdisease-associated neurotoxic mechanisms and neuroprotective strategies.Curr Drug Targets CNS Neurol Disord,2005,4(4):383-403.
[10] Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev,2001,81(2):741-766.
[11] Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B.Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.Am J Pathol,1994,145(5):1030-1035.
[12] Ma J, Yee A, Brewer HB Jr. Das S, Potter H. Amyloid-associated proteinsα1-antichymotrypsin and apolipoprotein E promote the assembly of theAlzheimer β-protein into filaments. Nature,1994,372:92-94.
[13] Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, AndersonDH. The Alzheimer's A beta-peptide is deposited at sites of complementactivation in pathologic deposits associated with aging and age-relatedmacular degeneration. Proc Natl Acad Sci USA,2002,99(18):11830-11835.
[14] Boyett KW, DiCarlo G, Jantzen PT, Jackson J, O'Leary C, Wilcock D,Morgan D, Gordon MN. Increased fibrillar beta-amyloid in response tohuman clq injections into hippocampus and cortex of APP+PS1transgenicmice. Neurochem Res,2003,28(1):83-93.
[15] Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM. Abetaoligomer-mediated long-term potentiation impairment involves proteinphosphatase1-dependent mechanisms. J Neurosci,2007,27(29):7648-7653.
[16] Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding:gain-and loss-of-function in neurodegenerative diseases. Embo J,2008,27(2):336-349.
[17] Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I,Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM,Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directlyfrom Alzheimer's brains impair synaptic plasticity and memory. Nat Med,2008,14(8):837-842.
[18] Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, AisoS. Amyloid-beta causes memory impairment by disturbing theJAK2/STAT3axis in hippocampal neurons. Mol Psychiatry,2009,14(2):206-222.
[19] Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP bindsDR6to trigger axon pruning and neuron death via distinct caspases. Nature,2009,457(7232):981-989.
[20] Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease.Hypothesis: Alzheimer's disease is caused by the cerebral accumulationand cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci,2000,924:17-25.
[21] Lleo A, Greenberg SM, Growdon JH. Current pharmacotherapy forAlzheimer's disease. Annu Rev Med,2006,57:513-533.
[22] Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM.Immunotherapy targeting pathological tau conformers in a tangle mousemodel reduces brain pathology with associated functional improvements. JNeurosci,2007,27(34):9115-9129.
[23] Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M,Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G,Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A,Frebourg T. Early-onset autosomal dominant Alzheimer disease:prevalence, genetic heterogeneity, and mutation spectrum. Am J HumGenet,1999,65:664-70.
[24] Iqbal K, Grundke-Iqbal I. Metabolic/signal transduction hypothesis ofAlzheimer’s disease and other tauopathies. Acta Neuropathol (Berl),2005,109:25-31.
[25] Braak H, Braak E, Grundke-Iqbal I, Iqbal K. Occurrence of neuropilthreads in the senile human brain and in Alzheimer’s disease: a thirdlocation of paired helical filaments outside of neurofibrillary tangles andneuritic plaques. Neurosci Lett,1986,65:351-5.
[26] Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helicalfilaments inAlzheimer’s disease. Science,1987,235:1641-4.
[27] Perry G, Friedman R, Shaw G, Chau V. Ubiquitin is detected inneurofibrillary tangles and senile plaque neurites of Alzheimer diseasebrains. Proc Natl Acad Sci USA,1987,84:3033-6.
[28] Wang GP, Khatoon S, Iqbal K, Grundke-Iqbal I. Brain ubiquitin ismarkedly elevated in Alzheimer disease. Brain Res,1991,566:146-51.
[29] Selkoe DJ. Defining molecular targets to prevent Alzheimer disease. ArchNeurol,2005,62:192-5.
[30] Iqbal K, Grundke-Iqbal I. Developing pharmacological therapies forAlzheimer disease. Cell Mol Life Sci,2007,64:2234-44.
[31] Hardy J. A hundred years of Alzheimer’s disease research. Neuron,2006,52:3-13.
[32] Alafuzoff I, Iqbal K, Friden H, Adolfsson R, Winblad B. Histopathologicalcriteria for progressive dementia disorders: clinical-pathologicalcorrelation and classification by multivariate data analysis. ActaNeuropathol (Berl),1987,74:209-25.
[33] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT.Neurofibrillary tangles but not senile plaques parallel duration and severityofAlzheimer’s disease. Neurology,1992,42:631-9.
[34] Tomlinson BE, Blessed G, Roth M. Observations on the brains ofdemented old people. J Neurol Sci,1970,11:205-42.
[35] Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH. Alzheimer’sdisease. A doublelabeling immunohistochemical study of senile plaques.Am J Pathol,1988,132:86-101.
[36] Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P,Yen SH, Aronson MK. Identification of normal and pathological aging inprospectively studied nondemented elderly humans. Neurobiol Aging,1992,13:179-89.
[37] Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X,Peck A. Clinical, pathological, and neurochemical changes in dementia: asubgroup with preserved mental status and numerous neocortical plaques.Ann Neurol,1988,23:138-44.
[38] Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H,Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J,Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, deGraaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM,Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, BasunH, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR,Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D,Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D,Lynch T, Heutink P. Association of missense and5′-splice-site mutations intau with the inherited dementia FTDP-17. Nature,1998,393:702-5.
[39] Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L,Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is acandidate gene for17frontotemporal dementia. Ann Neurol,1998,43:815-25.
[40] Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B.Mutation in the tau gene in familial multiple system tauopathy withpresenile dementia. Proc Natl Acad Sci USA,1998,95:7737-41.
[41] Alonso AD, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K.Promotion of hyperphosphorylation by frontotemporal dementia taumutations. J Biol Chem,2004,279:34873-81.
[42] Iqbal K, Zaidi T, Bancher C, Grundke-Iqbal I. Alzheimer paired helicalfilaments. Restoration of the biological activity by dephosphorylation.FEBS. Lett.,1994,349:104-8.
[43] Khatoon S, Grundke-Iqbal I, Iqbal K. Guanosine triphosphate binding tobeta-subunit of tubulin in Alzheimer’s disease brain: role ofmicrotubule-associated protein tau. J Neurochem,1995,64:777-87.
[44] Alonso AD, Li B, Grundke-Iqbal I, Iqbal K. Polymerization ofhyperphosphorylated tau into filaments eliminates its inhibitory activity.Proc. Natl. Acad. Sci USA.,2006,23:8864-9.
[45] Li B, Chohan MO, Grundke-Iqbal I, Iqbal K. Disruption of microtubulenetwork by Alzheimer abnormally hyperphosphorylated tau. ActaNeuropathol (Berl),2007,113:501-11.
[46] Alonso AD, Grundke-Iqbal I, Iqbal K. Alzheimer’s diseasehyperphosphorylated tau sequesters normal tau into tangles of filamentsand disassembles microtubules. Nat. Med.,1996,2:783-7.
[47] Alonso AD, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormallyphosphorylated tau in the breakdown of microtubules in Alzheimer disease.Proc. Natl. Acad. Sci. USA.,1994,91:5562-6.
[48] Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylationof Alzheimer paired helical filaments by protein phosphatase-2A and-2B. J.Biol. Chem.,1995,270:4854-60.
[49] Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity ofAlzheimer abnormally phosphorylated tau by dephosphorylation withprotein phosphatase-2A,-2B and-1. Brain Res. Mol. Brain Res.,1996,38:200-8.
[50] Le e G. Neve RI，Kosik KS．The microtubule binding domain of tau protein.Neuron,1982,(6):1615-24.
[51] Kosik KS, Orecchio LD, Bakalis S, Neve RL. Developmentally regulatedexpression of specific tau sequences. Neuron,1989,2(4):1389-97.
[52] Goedert, M. and Jakes, R.. Expression of separate isoforms of human tauprotein: correlation with the tau pattern in brain and effects on tubulinpolymerization. EMBO J,1990,9:4225-4230.
[53] Butner, K.A. and Kirschner, M.W.. Tau protein binds to microtubulesthrough a fexible array of distributed weak sites. J. Cell Biol.,1991,115:717-730.
[54] Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM.Abnormal tau phosphorylation at Ser396in Alzheimer's disease recapitulates development andcontributes to reduced microtubule binding. Neuron,1993,10(6):1089-99.
[55] Baas, P.W. and Qiang, L. Neuronal microtubules: when the MAP is theroadblock. Trends Cell Biol,2005,15:183-187.
[56] Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blockstraffic of organelles, neurofilaments, and APP vesicles in neurons andenhances oxidative stress. J Cell Biol,2002,156(6):1051-63.
[57] Goldsbury C, Mocanu MM, Thies E, Kaether C, Haass C, Keller P, BiernatJ, Mandelkow E, Mandelkow EM. Inhibition of APP trafficking by tauprotein does not increase the generation of amyloid-beta peptides.Traffic,2006,7(7):873-88.
[58] Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation ofdynein motor proteins by tau. Science,2008,319(5866):1086-9.
[59] Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging ofaxons by tau, inhibition of axonal traffic and starvation of synapses.Neurobiol Aging,2003,24(8):1079-85.
[60] Thies, E. and Mandelkow, E.M.. Missorting of tau in neurons causesdegeneration of synapses that can be rescued by the kinase MARK2/Par-1.J. Neurosci.,2007,27:2896-2907.
[61] Yuan, A. Kumar, A. Peterhoff, C. Duff, K. Nixon, R. A.. Axonal transportrates in vivo are unaffected by tau deletion or overexpression in mice. J.Neurosci.,2008,28:1682-1687.
[62] Konzack S, Thies E, Marx A, Mandelkow EM, Mandelkow E. Swimmingagainst the tide: mobility of the microtubule-associated protein tau inneurons. J Neurosci,2007,27(37):9916-27.
[63] Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA,Harkany T, Holzer M, Holzer M. Reversible paired helical filament-likephosphorylation of tau is an adaptive process associated with neuronalplasticity in hibernating animals. J Neurosci,2003,23(18):6972-81.
[64] Hartig, W. Stieler, J. Boerema, A. S. Wolf, J. Schmidt, U. Weissfuss, J.Bullmann, T. Strijkstra, A. M. Arendt, T. Hibernation model of tauphosphorylation in hamsters: selective vulnerability of cholinergic basalforebrain neurons-implications for Alzheimer’s disease. Eur. J. Neurosci.,2007,25:69-80.
[65] Planel E, Richter KE, Nolan CE, Finley JE, Liu L, Wen Y, KrishnamurthyP, Herman M, Wang L, Schachter JB, Nelson RB, Lau LF, Duff KE.Anesthesia leads to tau hyperphosphorylation through inhibition ofphosphatase activity by hypothermia. J. Neurosci.,2007,27:3090-3097.
[66] Bedford, P.D. Adverse cerebral effects of anaesthesia on old people. Lancet,1955,269:259-263.
[67] Ancelin ML, de Roquefeuil G, Ledésert B, Bonnel F, Cheminal JC, RitchieK. Exposure to anaesthetic agents, cognitive functioning and depressivesymptomatology in the elderly. Br. J. Psychiatry,2001,178:360-366.
[68] Henríquez JP, Cross D, Vial C, Maccioni RB. Subpopulations of tauinteract with microtubules and actin flaments in various cell types. CellBiochem. Funct,1995,13:239-250.
[69] Kempf M, Clement A, Faissner A, Lee G, Brandt R. Tau binds to the distalaxon early in development of polarity in a microtubule-andmicroflament-dependent manner. J. Neurosci.,1996,16:5583-5592.
[70] Brandt R, Léger J, Lee G. Interaction of tau with the neural plasmamembrane mediated by tau’s amino-terminal projection domain. J. CellBiol.,1995,131:1327-1340.
[71] Maas T, Eidenmüller J, Brandt R. Interaction of tau with the neuralmembrane cortex is regulated by phosphorylation at sites that are modifedin paired helical flaments. J. Biol. Chem.,2000,275:15733-15740.
[72] Baudier J, Lee SH, and Cole RD. Separation of the differentmicrotubule-associated tau protein species from bovine brain and theirmode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C.J Biol Chem,1987,262:17584-17590.
[73] Ihara Y, Nukina N, Miura R, and Ogawara M. Phosphorylated tau proteinis integrated into paired helical flaments in Alzheimer’s disease. JBiochem,1986,99:1807-1810.
[74] Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, BirdIN, Varndell IM, Sheppard PW, Everall I, and Anderton BH. Rapidtyrosine phosphorylation of neuronal proteins including tau and focaladhesion kinase in response to amyloid-beta peptide exposure:involvement of Src family protein kinases. J Neurosci,2002,22:10-20.
[75] Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcN Acylationregulates phosphorylation of tau: A mechanism involved in Alzheimer'sdisease. Proc Natl Acad Sci USA,2004,101(29):10804-10809.
[76] Lefebvre T, Ferreira S, Dupont-Wallois L, Bussiere T, Dupire MJ,Delacourte A, Michalski JC, Caillet-Boudin ML. Evidence of a balancebetween phosphorylation and O-GlcNAc glycosylation of tau proteins-Arole in nuclear localization. Biochim Biophys Acta,2003,1619(2):167-176.
[77] Hershko A and Ciechanover A. The ubiquitin system. Annu Rev Biochem,1998,67:425-479.
[78] Mayer A, Siegel NR, Schwartz AL, and Ciechanover A. Degradation ofproteins with acetylated amino termini by the ubiquitin system. Science,1989,244:1480-1483.
[79] Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW,Caputo C, Frappier T, Smith MA, Perry G, Yen SH, and Stem D. Glycatedtau protein in Alzheimer disease: a mechanism for induction of oxidantstress. Proc Natl Acad Sci USA,1994,91:7787-7791.
[80] Ledesma MD, Bonay P, and Avila J. Tau protein from Alzheimer’s diseasepatients is glycated at its tubulin-binding domain. J Neurochem,1995,65:1658-1664.
[81] Smith MA, Sayre LM, Monnier VM, and Perry G. Radical AGEing inAlzheimer’s disease. Trends Neurosci,1995,18:172-176.
[82] Wischik CM, Lai RYK, and Harrington CR. Modelling prion-likeprocessing of tau protein in Alzheimer’s disease for pharmaceuticaldevelopment. In: Brain Microtubule Associated, edited by Avila J, BrandtR, and Kosik KS. Chur, Switzerland: Harwood Academic,1997, p:185-241.
[83] Montejo de Garcini E, Serrano L, and Avila J. Self-assembly ofmicrotubule associated protein tau into flaments resembling those found inAlzheimer disease. Biochem Biophys Res Commun,1986,141:790-796.
[84] Frame S, Cohen P, and Biondi RM. A common phosphate binding siteexplains the unique substrate specifcity of GSK3and its inactivation byphosphorylation. Mol Cell,2001,7:1321-1327.
[85] Cho JH and Johnson GV. Glycogen synthase kinase3beta (GSK3beta)phosphorylates tau at both primed and unprimed sites: differential impacton microtubule binding. J Biol Chem,2002,278:187-193.
[86] Gong CX, Grundke-Iqbal I, and Iqbal K. Dephosphorylation ofAlzheimer’s disease abnormally phosphorylated tau by proteinphosphatase-2A. Neuroscience,1994,61:765-772.
[87] Gong CX, Singh TJ, Grundke-Iqbal I, and Iqbal K. Alzheimer’s diseaseabnormally phosphorylated tau is dephosphorylated by proteinphosphatase-2B (calcineurin). J Neurochem,1994,62:803-806.
[88] Goedert M, Jakes R, Qi Z, Wang JH, and Cohen P. Protein phosphatase2Ais the major enzyme in brain that dephosphorylates tau proteinphosphorylated by proline-directed protein kinases or cyclicAMP-dependent protein kinase. J Neurochem,1995,65:2804-2807.
[89] Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, and Iqbal K.Phosphorylation of microtubule-associated protein tau are regulated byprotein phosphatase2A in mammalian brain. Implications forneurofbrillary degeneration in Alzheimer’s disease. J Biol Chem,2000,275:5535-5544.
[90] Hyman BT, Augustinack JC, Ingelsson M. Transcriptional andconformational changes of the tau molecule in Alzheimer’s disease.Biochim. Biophys. Acta.,2005,1739:150-157.
[91] Lee, V. M. Goedert, M. Trojanowski, J. Q. Neurodegenerative tauopathies.Annu. Rev. Neurosci.,2001,24:1121-1159.
[92] Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G,Pickering-Brown S, Duff K, Hutton M.5' splice site mutations in tauassociated with the inherited dementia FTDP-17affect a stem-loopstructure that regulates alternative splicing of exon10. J. Biol. Chem.,1999,274:15134-15143.
[93] Varani L, Hasegawa M, Spillantini MG, Smith MJ, Murrell JR, Ghetti B,Klug A, Goedert M, Varani G. Structure of tau exon10splicing regulatoryelement RNA and destabilization by mutations of frontotemporal dementiaand parkinsonism linked to chromosome17. Proc. Natl. Acad. Sci. U. S. A.,1999,96:8229-8234.
[94] Conrad C, Zhu J, Conrad C, Schoenfeld D, Fang Z, Ingelsson M, Stamm S,Church G, Hyman BT. Single molecule profling of tau gene expression inAlzheimer’s disease. J. Neurochem.,2007,103:1228–1236.
[95] Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A.Different distribution of phosphorylated tau protein isoforms inAlzheimer’s and Pick’s diseases. FEBS Lett,1997,412:578-582.
[96] Stoothoff, W.H. and Johnson, G.V. Tau phosphorylation: physiological andpathological consequences. Biochim. Biophys. Acta.,2005,1739:280-297.
[97] Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, MeyerHE, Mandelkow EM, Mandelkow E. Microtubule-associatedprotein/microtubule affnity-regulating kinase (p110mark). A novel proteinkinase that regulates tau-microtubule interactions and dynamic instabilityby phosphorylation at the Alzheimer-specifc site serine262. J. Biol.Chem.,1995,270:7679-7688.
[98] Song, J.S. and Yang, S.D. Tau protein kinase I/GSK-3b/kinase FA inheparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369,and Ser400sites phosphorylated in Alzheimer disease brain. J. ProteinChem.,1995,14:95-105.
[99] Delacourte, A. Tau, a biological marker of neurodegenerative disease. InDementias,2008,89:161-172.
[100] Eidenmüller J, Fath T, Maas T, Pool M, Sontag E, Brandt R.Phosphorylation-mimicking glutamate clusters in the proline-rich regionare suffcient to simulate the functional defciencies ofhyperphosphorylated tau protein. Biochem. J.,2001,357:759-767.
[101] Fath T, Eidenmüller J, Brandt R. Tau-mediated cytotoxicity in apseudohyperphosphorylation model of Alzheimer’s disease. J. Neurosci.,2002,22:9733-9741.
[102] Léger J, Kempf M, Lee G, Brandt R. Conversion of serine to aspartateimitates phosphorylation-induced changes in the structure and function ofmicrotubule-associated protein tau. J. Biol. Chem.,1997,272:8441-8446.
[103] Kuret J, Congdon EE, Li G, Yin H, Yu X, Zhong Q. Evaluating triggers andenhancers of tau fbrillization. Microsc. Res. Tech.,2005,67:141-155.
[104] Alonso Adel C, Li B, Grundke-Iqbal I, Iqbal K. Polymerization ofhyperphosphorylated tau into flaments eliminates its inhibitory activity.Proc. Natl. Acad. Sci. U. S. A.,2006,103:8864-8869.
[105] Chun, W. and Johnson, G.V. Activation of glycogen synthase kinase3bpromotes the intermolecular association of tau. The use of fuorescenceresonance energy transfer microscopy. J. Biol. Chem.,2007,282:23410-23417.
[106] Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie LA, Head E.Lack of pathology in a triple transgenic mouse model of Alzheimer’sdisease after overexpression of the anti-apoptotic protein Bcl-2. J.Neurosci.,2008,28:3051-3059.
[107] Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging ofaxons by tau, inhibition of axonal traffc and starvation of synapses.Neurobiol Aging,2003,24:1079-1085.
[108] Kempf M, Clement A, Faissner A, Lee G, Brandt R. Tau binds to the distalaxon early in development of polarity in a microtubule-andmicroflament-dependent manner. J. Neurosci.,1996,16:5583-5592.
[109] Ferrari A, Hoerndli F, Baechi T, Nitsch RM, G tz J. beta-Amyloid inducespaired helical flament-like tau flaments in tissue culture. J. Biol. Chem.,2003,278:40162-40168.
[110] Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL,Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI,Cryns VL. Caspase cleavage of tau: linking amyloid and neurofbrillarytangles in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA.,2003,100:10032-10037.
[111] Rapoport, M. Dawson, H. N. Binder, L. I. Vitek, M. P. Ferreira, A. Tau isessential to beta-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci.USA.,2002,99:6364-6369.
[112] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abetaimmunotherapy leads to clearance of early, but not late,hyperphosphorylated tau aggregates via the proteasome. Neuron,2004,43:321-332.
[113] Woodgett, J.R.. A common denominator linking glycogen metabolism,nuclear oncogenes and development. TIBS,1991,16:177-181.
[114] Eldar-Finkelman, H., Argast, G.M., Foord, O., Fischer, E.H., Krebs, E.G..Expression and characterization of glycogen synthase kinase-3mutants andtheir effect on glycogen synthase activity in intact cells. Proc. Natl. Acad.Sci. USA,1996,93:10228-10233.
[115] Woodgett, J.R.. Molecular cloning and expression of glycogen synthasekinase-3: Factor A. EMBO J,1990,9:2431-2438.
[116] Pei, J.J., Tanaka, T., Tung, Y.C., Braak, E., Iqbal, K., Grundke-Iqbal, I..Distribution, levels, and activity of glycogen synthase kinase-3in theAlzheimer disease brain. J. Neuropathol. Exp. Neurol.,1997,56:70-78.
[117] Takahashi, M., Tomizawa, K., Kato, R., Sato, K., Uchida, T., Fujita, S.C.,Imahori, K.. Localization and developmental changes of t protein kinase I:glycogen synthase kinase-3b in rat brain. J. Neurochem.,1994,63:245-255.
[118] Grimes C. A. and Jope R. S. The multifaceted roles of glycogen synthasekinase3beta in cellular signaling. Prog. Neurobiol.,2001,65:391-426.
[119] Doble B. W. and Woodgett J. R. GSK-3: tricks of the trade for amulti-tasking kinase. J. Cell Sci.,2003,116:1175-1186.
[120] Hughes K., Nikolakaki E., Plyte E. S., Totty N. F. and Woodgett J. R.Modulation of the glycogen synthase kinase-3family by tyrosinephosphorylation. EMBO J,1993,12:803-808.
[121] Cook D., Fry J. M., Hughes K., Sumathipala R., Woodgett J. R. and Dale T.C. Wingless inactivates glycogen synthase kinase-3via an intracellularsignalling pathway which involves a protein kinase C. EMBO J,1996,15:4526-4536.
[122] Yost C., Farr3rd H. G., Pierce B. S., Ferkey M. D., Chen M. M. andKimelman D. GBP, an inhibitor of GSK-3, is implicated in Xenopusdevelopment and oncogenesis. Cell,1998,93:1031-1041.
[123] Hart J. M., Santos de los R., Albert N. I., Rubinfeld B. and Polakis P.Downregulation of beta-catenin by human Axin and its association withthe APC tumor suppressor B., beta-catenin and GSK3beta. Curr. Biol.,1998,8:573-581.
[124] Noort van M., Meeldijk J., Zee van der R., Destree O. and Clevers H. Wntsignaling controls the phosphorylation status of beta-catenin. J. Biol.Chem.,2002,277:17901-17905.
[125] M. P. Mattson. Cellular actions of beta-amyloid precursor protein and itssoluble and fibrillogenic derivatives. Physiol. Rev.,1997,77:1081-1132.
[126] Pangalos N. M., Jacobsen S. J. and Reinhart P. H. Disease modifyingstrategies for the treatment of Alzheimer’s disease targeted at modulatinglevels of the beta-amyloid peptide. Biochem. Soc. Trans.,2005,33:553-558.
[127] Kim HS, Kim EM, Lee JP, Park CH, Kim S, Seo JH, Chang KA, Yu E,Jeong SJ, Chong YH, Suh YH. C-terminal fragments of amyloid precursorprotein exert neurotoxicity by inducing glycogen synthase kinase-3betaexpression. FASEB J,2003,17:1951-1953.
[128] Rapoport M., Dawson N. H., Binder I. L., Vitek M. P. and Ferreira A. Tauis essential to beta-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci.USA,2002,99:6364-6369.
[129] Su Y, Ryder J, Li B, Wu X, Fox N, Solenberg P, Brune K, Paul S, Zhou Y,Liu F, Ni B. Lithium, a common drug for bipolar disorder treatment,regulates amyloid-beta precursor protein processing. Biochemistry,2004,43:6899-6908.
[130] Phiel J. C., Wilson A. C., Lee V. M. and Klein P. S. GSK-3alpha regulatesproduction of Alzheimer’s disease amyloid-beta peptides. Nature,2003,423:435-439.
[131] Xia W., Zhang J., Perez R., Koo E. H. and Selkoe D. J. Interaction betweenamyloid precursor protein and presenilins in mammalian cells:implications for the pathogenesis of Alzheimer disease. Proc. Natl. Acad.Sci. USA,1997,94:8208-8213.
[132] Weihl C. C., Ghadge D. G., Kennedy G. S., Hay N., Miller R. J. and RoosR. P. Mutant presenilin-1induces apoptosis and downregulates Akt/PKB. J.Neurosci.,1999,19:5360-5369.
[133] Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K,Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B.Presenilin1associates with glycogen synthase kinase-3beta and itssubstrate tau. Proc. Natl. Acad. Sci. USA,1998,95:9637-9641.
[134] Kirschenbaum F., Hsu C. S., Cordell B. and McCarthy J. V. Substitution ofa glycogen synthase kinase-3beta phosphorylation site in presenilin1separates presenilin function from beta-catenin signaling. J. Biol. Chem.,2001,276:7366-7375.
[135] Kirschenbaum F., Hsu C. S., Cordell B. and McCarthy J. V. Glycogensynthase kinase-3beta regulates presenilin1C-terminal fragment levels. J.Biol. Chem.,2001,276:30701-30707.
[136] Flaherty B. D., Soria P. J., Tomasiewicz H. G. and Wood J. G.Phosphorylation of human tau protein by microtubule associated kinases:GSK3beta and cdk5are key participants. J. Neurosci. Res.,2000,62:463-472.
[137] Ishiguro K, Omori A, Takamatsu M, Sato K, Arioka M, Uchida T, ImahoriK. Phosphorylation sites on tau by tau protein kinase I, a bovine derivedkinase generating an epitope of paired helical filaments. Neurosci. Lett.,1992,148:202-206.
[138] Imahori K, Hoshi M, Ishiguro K, Sato K, Takahashi M, Shiurba R,Yamaguchi H, Takashima A, Uchida T. Possible role of tau protein kinasesin pathogenesis of Alzheimer’s disease. Neurobiology Aging,1998,19:S93-S98.
[139] Pap M. and Cooper G. M. Role of glycogen synthase kinase-3in thephosphatidylinositol3-kinase/Akt cell survival pathway. J. Biol. Chem.,1998,273:19929-19932.
[140] Karelle Leroy, Jean-Pierre Brion. Developmental expression andlocalization of glycogen synthase kinase-3b in rat brain. Journal ofChemical Neuroanatomy,1999,16:279-293.
[141] V. Janssens, J.Goris. Protein phosphatase2A: a highly regulated family ofserine/threonine phosphatases implicated in cell growth and signaling.Biochem. J.,2001,53:417-439.
[142] P. T. W. Cohen, N. D. Brewis, V. Hughes, D. J. Mann. Proteinserine/threonine phosphatases; an expanding family. FEBS Lett,1990,268:355-359.
[143] P. Agostinis, J. Goris, L.A. Pinna, F.M. archiori, J.W. Perich, H.E.Meyer, W.Merlevede. Synthetic peptides as model substrates for the study of thespecifcity of the polycation-stimulated protein phosphatases. Eur. J.Biochem.,1990,189:235-241.
[144] F. Liu, I. Grundke-Iqbal, K. Iqbal, C.X. Gong. Contributions of proteinphosphatases PP1, PP2A, PP2B and PP5to the regulation of tauphosphorylation. Eur. J. Neurosci.,2005,22:1942-1950.
[145] E. Sontag, V. Nunbhakdi-Craig, J.M. Sontag, R. Diaz-Arrastia, E.Ogris, S.Dayal, S.R. Lentz, E. Arning, T. Bottiglieri. Protein phosphatase2Amethyltransferase links homocysteine metabolism with tau and amyloidprecursor protein regulation. J. Neurosci.,2007,27:2751-2759.
[146] S. Kins, A. Crameri, D. R. Evans, B. A. Hemmings, R. M. Nitsch, J. Gotz.Reduced protein phosphatase2A activity induces hyperphosphorylationand altered compartmentalization of tau in transgenicmice. J. Biol. Chem.,2001,276:38193-38200.
[147] S. E. Gandy, G. L. Caporaso, J. D. Buxbaum, S. O. de Cruz, K. Iverfeldt, C.Nordstedt, T. Suzuki, A. J. Czernik, A. C. Nairn, P. Greengard. Proteinphosphorylation regulates relative utilization of processing pathways forAlzheimer beta/A4amyloid precursor protein. Ann. N.Y. Acad. Sci.,1993,695:117-121.
[148] J.D. Buxbaum, E.H. Koo, P. Greengard. Protein phosphorylation inhibitsproduction of Alzheimer amyloid beta/A4peptide. Proc. Natl. Acad. Sci.U.S.A.,1993,90:9195-9198.
[149] T. Arendt, M. Holzer, R. Fruth, M.K. Bruckner, U. Gartner.Phosphorylation of tau, Abeta formation, and apoptosis after in vivoinhibition of PP-1and PP-2A. Neurobiol. Aging,1998,19:3-13.
[150] K. Ando, K. I. Iijima, J. I. Elliott, Y. Kirino, T. Suzuki. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein withFe65affects the production of beta-amyloid. J. Biol. Chem.,2001,276:40353-40361.
[151] V. Vogelsberg-Ragaglia, T. Schuck, J.Q. Trojanowski, V.M. Lee. PP2AmRNA expression is quantitatively decreased in Alzheimer’s diseasehippocampus. Exp. Neurol.,2001,168:402-412.
[152] E. Sontag, A. Luangpirom, C. Hladik, I.Mudrak, E. Ogris, S. Speciale,C.L.White III. Altered expression levels of the protein phosphatase2AABalphaC enzyme are associated with Alzheimer disease pathology. J.Neuropathol. Exp. Neurol.,2004,63:287-301.
[153] R. Liu, X.W. Zhou, H. Tanila, C. Bjorkdahl, J.Z. Wang, Z.Z. Guan, Y. Cao,J.A. Gustafsson, B. Winblad, J.J. Pei. Phosphorylated PP2A (tyrosine307)is associated with Alzheimer neurofbrillary pathology. J. Cell. Mol. Med.,2008,12:241-257.
[154] E. Sontag, V. Nunbhakdi-Craig, G. Lee, G.S. Bloom, M.C. Mumby.Regulation of the phosphorylation state andmicrotubule-binding activity ofTau by protein phosphatase2A. Neuron,1996,17:1201-1207.
[155] M. Li, H. Guo, Z. Damuni. Purifcation and characterization of two potentheat-stable protein inhibitors of protein phosphatase2A from bovinekidney. Biochemistry,1995,34:1988-1996.
[156] S. Chen, B. Li, I. Grundke-Iqbal, K. Iqbal. I1PP2A affects tauphosphorylation via associationwith the catalytic subunit of proteinphosphatase2A. J. Biol. Chem.,2008,283:10513-10521.
[157] H. Tanimukai, I. Grundke-Iqbal, K. Iqbal. Up-regulation of inhibitors ofprotein phosphatase-2A in Alzheimer’s disease. Am. J. Pathol.,2005,166:1761-1771.
[158] E. Sontag. Protein phosphatase2A: the Trojan Horse of cellular signaling.Cell. Signal.,2001,13:7-16.
[159] E. Sontag, C. Hladik, L. Montgomery, A. Luangpirom, I. Mudrak, E. Ogris,C.L. White III. Downregulation of protein phosphatase2A carboxylmethylation and methyltransferase may contribute to Alzheimer diseasepathogenesis. J. Neuropathol. Exp. Neurol.,2004,63:1080-1091.
[160] X.W. Zhou, J.A. Gustafsson, H. Tanila, C. Bjorkdahl, R. Liu, B. Winblad,J.J. Pei. Tau hyperphosphorylation correlates with reduced methylation ofprotein phosphatase2A. Neurobiol. Dis.,2008,31:386-394.
[161] H. Guo, S.A. Reddy, Z. Damuni. Purifcation and characterization of anautophosphorylation-activated protein serine threonine kinase thatphosphorylates and inactivates protein phosphatase2A. J. Biol. Chem.,1993,268:11193-11198.
[162] Wang L, Zhang Y, Wang Z, Li S, Min G, Wang L, Chen J, Cheng J, Wu Y.Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammationin rats. Can J Physiol Pharmacol,2012,90(2):229-36.
[163] Yang XL, Guo TK, Wang YH, Huang YH, Liu X, Wang XX, Li W, ZhaoX, Wang LP, Yan S, Wu D, Wu YJ. Ginsenoside Rd attenuates theinflammatory response via modulating p38and JNK signaling pathways inrats with TNBS-induced relapsing colitis. Int Immunopharmacol,2012,12(2):408-14.
[164] Lin WM, Zhang YM, Moldzio R, Rausch WD. Ginsenoside Rd attenuatesneuroinflammation of dopaminergic cells in culture. J Neural TransmSuppl,2007,72:105-12.
[165] Li SY, Wang XG, Ma MM, Liu Y, Du YH, Lv XF, Zhou JG, TangYB, Guan YY. Ginsenoside-Rd potentiates apoptosis induced by hydrogenperoxide in basilar artery smooth muscle cells through the mitochondrialpathway. Apoptosis,2012,17(2):113-20.
[166] Ye R, Zhang X, Kong X, Han J, Yang Q, Zhang Y, Chen Y, Li P, Liu J, ShiM, Xiong L, Zhao G. Ginsenoside Rd attenuates mitochondrial dysfunctionand sequential apoptosis after transient focal ischemia. Neuroscience,2011,78:169-80.
[167] Li XY, Liang J, Tang YB, Zhou JG, Guan YY. Ginsenoside Rd preventsglutamate-induced apoptosis in rat cortical neurons. Clin Exp PharmacolPhysiol,2010,37(2):199-204.
[168] Tamura T, Cui X, Sakaguchi N, Akashi M. Ginsenoside Rd prevents andrescues rat intestinal epithelial cells from irradiation-induced apoptosis.Food Chem Toxicol,2008,46(9):3080-9.
[169] Yang ZG, Sun HX, Ye YP. Ginsenoside Rd from Panax notoginseng iscytotoxic towards HeLa cancer cells and induces apoptosis. ChemBiodivers,2006,3(2):187-97.
[170] Zhang Y, Zhou L, Zhang X, Bai J, Shi M, Zhao G. Ginsenoside-Rd attenuates TRPM7and ASIC1a but promotes ASIC2a expression in ratsafter focal cerebral ischemia. Neurol Sci,2012, Jan10.
[171] Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, Ma L, Cao R, Rao
[172] Z, Zhao G. Ginsenoside Rd protects neurons against glutamate-inducedexcitotoxicity by inhibiting Ca2+influx. Cell Mol Neurobiol,2012,32(1):121-8.
[173] Wang L, Zhang Y, Chen J, Li S, Wang Y, Hu L, Wang L, Wu Y.Immunosuppressive Effects of Ginsenoside-Rd on Skin Allograft Rejectionin Rats. J Surg Res,2011, Jul21.
[174] Li L, Liu J, Yan X, Qin K, Shi M, Lin T, Zhu Y, Kang T, Zhao G. Protectiveeffects of ginsenoside Rd against okadaic acid-induced neurotoxicity invivo and in vitro. J Ethnopharmacol,2011, Oct31,138(1):135-41.
[175] Liu X, Xia J, Wang L, Song Y, Yang J, Yan Y, Ren H, Zhao G. Efficacy andsafety of ginsenoside-Rd for acute ischaemic stroke: a randomized,double-blind, placebo-controlled, phase II multicenter trial. Eur JNeurol,2009,16(5):569-75.
[176] Liu X, Wang L, Wen A, Yang J, Yan Y, Song Y, Liu X, Ren H, Wu Y, LiZ, Chen W, Xu Y, Li L, Xia J, Zhao G. Ginsenoside-Rd improves outcomeof acute ischaemic stroke-a randomized, double-blind, placebo-controlled,multicenter trial. Eur J Neurol,2012, Jan10.
[177] Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K,Aksenov M, Aksenova M, Subramaniam R, Varadarajan S, Harris-WhiteME, Pedigo NW Jr, Carney JM. Elevated oxidative stress in models ofnormal brain aging and Alzheimer’s disease. Life Sci,1999,65(18):1883-1892.
[178] Choi SS, Lee JK, Han EJ, Han KJ, Lee HK, Lee J, Suh HW. Effect ofginsenoside Rd on nitric oxide system induced by lipopolysaccharide plusTNF-alpha in C6rat glioma cells. Arch Pharm Res,2003,26(5):375-82.
[179] Goedert, M. and Spillantini, M.G. A century of Alzheimer’s disease.Science,2006,314:777-781.
[180] Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, Avila J.Current advances on different kinases involved in tau phosphorylation, andimplications in Alzheimer's disease and tauopathies. Curr Alzheimer Res,2005,2(1):3-18.
[181] Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH. Glycogensynthase kinase-3induces Alzheimer’s disease-like phosphorylation of tau:generation of paired helical filament epitopes and neuronal localisation ofthe kinase. Neurosci. Lett.,1992,147:58-62.
[182] Drewes G, Mandelkow EM, Baumann K, Goris J, Merlevede W,Mandelkow E. Dephosphorylation of tau protein and Alzheimer pairedhelical filaments by calcineurin and phosphatase-2A. FEBS Lett,1993,336:425-432.
[183] Liu F, Liang Z, Shi J, Yin D, El-Akkad E, Grundke-Iqbal I, Iqbal K, GongCX. PKA modulates GSK-3beta-and cdk5-catalyzed phosphorylation oftau in site-and kinase-specific manners. FEBS Lett,2006,580(26):6269-74.
[184] J. Q. Trojanowski, V. M. Lee. Phosphorylation of paired helical filamenttau in Alzheimer’s disease neurofibrillary lesions: focusing onphosphatases. FASEB J,1995,9:1570-1576.
[185] Kazuo, T., Paul, J. S., Yasumasa, T., Hiroyuki, K., Donna, V. E., Jon, C.,Yalamanchili, G., Francis, J. S..“Okadaic acid, a cytotoxic polyether fromtwo marine sponges of the genus Halichondria”. Journal of the AmericanChemical Society,1981,103:2469-2471.
[186] Alphonse, G., Xavier, C., Julien, G., Frédéric, D., Véronique, H., Maria, P.R., Aarne, F., Angelita, R..“Serine/threonine protein phosphatases PP1andPP2Aare key players in apoptosis”. Biochimie,2003,85:721-726.
[2] Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL,Beyreuther K. Amyloid plaque core protein in Alzheimer disease andDown syndrome. Proc Natl Acad Sci USA,1985,82:4245-9.
[3] Miller DL, Papayannopoulos IA, Styles J, Bobin SA, Lin YY, Biemann K,Iqbal K. Peptide compositions of the cerebrovascular and senile plaquecore amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys,1993,301:41-52.
[4] Iqbal K, Wisniewski HM, Shelanski ML, Brostoff S, Liwnicz BL, TerryRD. Protein changes in senile dementia. Brain Res,1974,77:337-43.
[5] Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, WisniewskiHM. Microtubule-associated protein tau. A component of Alzheimer pairedhelical filaments. J. Biol. Chem.,1986,261:6084-9.
[6] Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, BinderLI. Abnormal phosphorylation of the microtubule-associated protein tau(tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. USA.,1986,83:4913-7.
[7] Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS,Wisniewski HM, Alafuzoff I, Winblad B. Defective brain microtubuleassembly in Alzheimer’s disease. Lancet,1986,2:421-6.
[8] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease:progress and problems on the road to therapeutics. Science,2002,297(5580):353-356.
[9] Pereira C, Agostinho P, Moreira PI, Cardoso SM, Oliveira CR. Alzheimer'sdisease-associated neurotoxic mechanisms and neuroprotective strategies.Curr Drug Targets CNS Neurol Disord,2005,4(4):383-403.
[10] Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev,2001,81(2):741-766.
[11] Wisniewski T, Castano EM, Golabek A, Vogel T, Frangione B.Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.Am J Pathol,1994,145(5):1030-1035.
[12] Ma J, Yee A, Brewer HB Jr. Das S, Potter H. Amyloid-associated proteinsα1-antichymotrypsin and apolipoprotein E promote the assembly of theAlzheimer β-protein into filaments. Nature,1994,372:92-94.
[13] Johnson LV, Leitner WP, Rivest AJ, Staples MK, Radeke MJ, AndersonDH. The Alzheimer's A beta-peptide is deposited at sites of complementactivation in pathologic deposits associated with aging and age-relatedmacular degeneration. Proc Natl Acad Sci USA,2002,99(18):11830-11835.
[14] Boyett KW, DiCarlo G, Jantzen PT, Jackson J, O'Leary C, Wilcock D,Morgan D, Gordon MN. Increased fibrillar beta-amyloid in response tohuman clq injections into hippocampus and cortex of APP+PS1transgenicmice. Neurochem Res,2003,28(1):83-93.
[15] Knobloch M, Farinelli M, Konietzko U, Nitsch RM, Mansuy IM. Abetaoligomer-mediated long-term potentiation impairment involves proteinphosphatase1-dependent mechanisms. J Neurosci,2007,27(29):7648-7653.
[16] Winklhofer KF, Tatzelt J, Haass C. The two faces of protein misfolding:gain-and loss-of-function in neurodegenerative diseases. Embo J,2008,27(2):336-349.
[17] Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I,Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM,Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directlyfrom Alzheimer's brains impair synaptic plasticity and memory. Nat Med,2008,14(8):837-842.
[18] Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, AisoS. Amyloid-beta causes memory impairment by disturbing theJAK2/STAT3axis in hippocampal neurons. Mol Psychiatry,2009,14(2):206-222.
[19] Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP bindsDR6to trigger axon pruning and neuron death via distinct caspases. Nature,2009,457(7232):981-989.
[20] Selkoe DJ. Toward a comprehensive theory for Alzheimer's disease.Hypothesis: Alzheimer's disease is caused by the cerebral accumulationand cytotoxicity of amyloid beta-protein. Ann N Y Acad Sci,2000,924:17-25.
[21] Lleo A, Greenberg SM, Growdon JH. Current pharmacotherapy forAlzheimer's disease. Annu Rev Med,2006,57:513-533.
[22] Asuni AA, Boutajangout A, Quartermain D, Sigurdsson EM.Immunotherapy targeting pathological tau conformers in a tangle mousemodel reduces brain pathology with associated functional improvements. JNeurosci,2007,27(34):9115-9129.
[23] Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M,Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G,Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A,Frebourg T. Early-onset autosomal dominant Alzheimer disease:prevalence, genetic heterogeneity, and mutation spectrum. Am J HumGenet,1999,65:664-70.
[24] Iqbal K, Grundke-Iqbal I. Metabolic/signal transduction hypothesis ofAlzheimer’s disease and other tauopathies. Acta Neuropathol (Berl),2005,109:25-31.
[25] Braak H, Braak E, Grundke-Iqbal I, Iqbal K. Occurrence of neuropilthreads in the senile human brain and in Alzheimer’s disease: a thirdlocation of paired helical filaments outside of neurofibrillary tangles andneuritic plaques. Neurosci Lett,1986,65:351-5.
[26] Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helicalfilaments inAlzheimer’s disease. Science,1987,235:1641-4.
[27] Perry G, Friedman R, Shaw G, Chau V. Ubiquitin is detected inneurofibrillary tangles and senile plaque neurites of Alzheimer diseasebrains. Proc Natl Acad Sci USA,1987,84:3033-6.
[28] Wang GP, Khatoon S, Iqbal K, Grundke-Iqbal I. Brain ubiquitin ismarkedly elevated in Alzheimer disease. Brain Res,1991,566:146-51.
[29] Selkoe DJ. Defining molecular targets to prevent Alzheimer disease. ArchNeurol,2005,62:192-5.
[30] Iqbal K, Grundke-Iqbal I. Developing pharmacological therapies forAlzheimer disease. Cell Mol Life Sci,2007,64:2234-44.
[31] Hardy J. A hundred years of Alzheimer’s disease research. Neuron,2006,52:3-13.
[32] Alafuzoff I, Iqbal K, Friden H, Adolfsson R, Winblad B. Histopathologicalcriteria for progressive dementia disorders: clinical-pathologicalcorrelation and classification by multivariate data analysis. ActaNeuropathol (Berl),1987,74:209-25.
[33] Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT.Neurofibrillary tangles but not senile plaques parallel duration and severityofAlzheimer’s disease. Neurology,1992,42:631-9.
[34] Tomlinson BE, Blessed G, Roth M. Observations on the brains ofdemented old people. J Neurol Sci,1970,11:205-42.
[35] Dickson DW, Farlo J, Davies P, Crystal H, Fuld P, Yen SH. Alzheimer’sdisease. A doublelabeling immunohistochemical study of senile plaques.Am J Pathol,1988,132:86-101.
[36] Dickson DW, Crystal HA, Mattiace LA, Masur DM, Blau AD, Davies P,Yen SH, Aronson MK. Identification of normal and pathological aging inprospectively studied nondemented elderly humans. Neurobiol Aging,1992,13:179-89.
[37] Katzman R, Terry R, DeTeresa R, Brown T, Davies P, Fuld P, Renbing X,Peck A. Clinical, pathological, and neurochemical changes in dementia: asubgroup with preserved mental status and numerous neocortical plaques.Ann Neurol,1988,23:138-44.
[38] Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H,Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J,Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, deGraaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM,Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, BasunH, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR,Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D,Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D,Lynch T, Heutink P. Association of missense and5′-splice-site mutations intau with the inherited dementia FTDP-17. Nature,1998,393:702-5.
[39] Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L,Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is acandidate gene for17frontotemporal dementia. Ann Neurol,1998,43:815-25.
[40] Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B.Mutation in the tau gene in familial multiple system tauopathy withpresenile dementia. Proc Natl Acad Sci USA,1998,95:7737-41.
[41] Alonso AD, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K.Promotion of hyperphosphorylation by frontotemporal dementia taumutations. J Biol Chem,2004,279:34873-81.
[42] Iqbal K, Zaidi T, Bancher C, Grundke-Iqbal I. Alzheimer paired helicalfilaments. Restoration of the biological activity by dephosphorylation.FEBS. Lett.,1994,349:104-8.
[43] Khatoon S, Grundke-Iqbal I, Iqbal K. Guanosine triphosphate binding tobeta-subunit of tubulin in Alzheimer’s disease brain: role ofmicrotubule-associated protein tau. J Neurochem,1995,64:777-87.
[44] Alonso AD, Li B, Grundke-Iqbal I, Iqbal K. Polymerization ofhyperphosphorylated tau into filaments eliminates its inhibitory activity.Proc. Natl. Acad. Sci USA.,2006,23:8864-9.
[45] Li B, Chohan MO, Grundke-Iqbal I, Iqbal K. Disruption of microtubulenetwork by Alzheimer abnormally hyperphosphorylated tau. ActaNeuropathol (Berl),2007,113:501-11.
[46] Alonso AD, Grundke-Iqbal I, Iqbal K. Alzheimer’s diseasehyperphosphorylated tau sequesters normal tau into tangles of filamentsand disassembles microtubules. Nat. Med.,1996,2:783-7.
[47] Alonso AD, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormallyphosphorylated tau in the breakdown of microtubules in Alzheimer disease.Proc. Natl. Acad. Sci. USA.,1994,91:5562-6.
[48] Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylationof Alzheimer paired helical filaments by protein phosphatase-2A and-2B. J.Biol. Chem.,1995,270:4854-60.
[49] Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity ofAlzheimer abnormally phosphorylated tau by dephosphorylation withprotein phosphatase-2A,-2B and-1. Brain Res. Mol. Brain Res.,1996,38:200-8.
[50] Le e G. Neve RI，Kosik KS．The microtubule binding domain of tau protein.Neuron,1982,(6):1615-24.
[51] Kosik KS, Orecchio LD, Bakalis S, Neve RL. Developmentally regulatedexpression of specific tau sequences. Neuron,1989,2(4):1389-97.
[52] Goedert, M. and Jakes, R.. Expression of separate isoforms of human tauprotein: correlation with the tau pattern in brain and effects on tubulinpolymerization. EMBO J,1990,9:4225-4230.
[53] Butner, K.A. and Kirschner, M.W.. Tau protein binds to microtubulesthrough a fexible array of distributed weak sites. J. Cell Biol.,1991,115:717-730.
[54] Bramblett GT, Goedert M, Jakes R, Merrick SE, Trojanowski JQ, Lee VM.Abnormal tau phosphorylation at Ser396in Alzheimer's disease recapitulates development andcontributes to reduced microtubule binding. Neuron,1993,10(6):1089-99.
[55] Baas, P.W. and Qiang, L. Neuronal microtubules: when the MAP is theroadblock. Trends Cell Biol,2005,15:183-187.
[56] Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blockstraffic of organelles, neurofilaments, and APP vesicles in neurons andenhances oxidative stress. J Cell Biol,2002,156(6):1051-63.
[57] Goldsbury C, Mocanu MM, Thies E, Kaether C, Haass C, Keller P, BiernatJ, Mandelkow E, Mandelkow EM. Inhibition of APP trafficking by tauprotein does not increase the generation of amyloid-beta peptides.Traffic,2006,7(7):873-88.
[58] Dixit R, Ross JL, Goldman YE, Holzbaur EL. Differential regulation ofdynein motor proteins by tau. Science,2008,319(5866):1086-9.
[59] Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging ofaxons by tau, inhibition of axonal traffic and starvation of synapses.Neurobiol Aging,2003,24(8):1079-85.
[60] Thies, E. and Mandelkow, E.M.. Missorting of tau in neurons causesdegeneration of synapses that can be rescued by the kinase MARK2/Par-1.J. Neurosci.,2007,27:2896-2907.
[61] Yuan, A. Kumar, A. Peterhoff, C. Duff, K. Nixon, R. A.. Axonal transportrates in vivo are unaffected by tau deletion or overexpression in mice. J.Neurosci.,2008,28:1682-1687.
[62] Konzack S, Thies E, Marx A, Mandelkow EM, Mandelkow E. Swimmingagainst the tide: mobility of the microtubule-associated protein tau inneurons. J Neurosci,2007,27(37):9916-27.
[63] Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee EA,Harkany T, Holzer M, Holzer M. Reversible paired helical filament-likephosphorylation of tau is an adaptive process associated with neuronalplasticity in hibernating animals. J Neurosci,2003,23(18):6972-81.
[64] Hartig, W. Stieler, J. Boerema, A. S. Wolf, J. Schmidt, U. Weissfuss, J.Bullmann, T. Strijkstra, A. M. Arendt, T. Hibernation model of tauphosphorylation in hamsters: selective vulnerability of cholinergic basalforebrain neurons-implications for Alzheimer’s disease. Eur. J. Neurosci.,2007,25:69-80.
[65] Planel E, Richter KE, Nolan CE, Finley JE, Liu L, Wen Y, KrishnamurthyP, Herman M, Wang L, Schachter JB, Nelson RB, Lau LF, Duff KE.Anesthesia leads to tau hyperphosphorylation through inhibition ofphosphatase activity by hypothermia. J. Neurosci.,2007,27:3090-3097.
[66] Bedford, P.D. Adverse cerebral effects of anaesthesia on old people. Lancet,1955,269:259-263.
[67] Ancelin ML, de Roquefeuil G, Ledésert B, Bonnel F, Cheminal JC, RitchieK. Exposure to anaesthetic agents, cognitive functioning and depressivesymptomatology in the elderly. Br. J. Psychiatry,2001,178:360-366.
[68] Henríquez JP, Cross D, Vial C, Maccioni RB. Subpopulations of tauinteract with microtubules and actin flaments in various cell types. CellBiochem. Funct,1995,13:239-250.
[69] Kempf M, Clement A, Faissner A, Lee G, Brandt R. Tau binds to the distalaxon early in development of polarity in a microtubule-andmicroflament-dependent manner. J. Neurosci.,1996,16:5583-5592.
[70] Brandt R, Léger J, Lee G. Interaction of tau with the neural plasmamembrane mediated by tau’s amino-terminal projection domain. J. CellBiol.,1995,131:1327-1340.
[71] Maas T, Eidenmüller J, Brandt R. Interaction of tau with the neuralmembrane cortex is regulated by phosphorylation at sites that are modifedin paired helical flaments. J. Biol. Chem.,2000,275:15733-15740.
[72] Baudier J, Lee SH, and Cole RD. Separation of the differentmicrotubule-associated tau protein species from bovine brain and theirmode II phosphorylation by Ca2+/phospholipid-dependent protein kinase C.J Biol Chem,1987,262:17584-17590.
[73] Ihara Y, Nukina N, Miura R, and Ogawara M. Phosphorylated tau proteinis integrated into paired helical flaments in Alzheimer’s disease. JBiochem,1986,99:1807-1810.
[74] Williamson R, Scales T, Clark BR, Gibb G, Reynolds CH, Kellie S, BirdIN, Varndell IM, Sheppard PW, Everall I, and Anderton BH. Rapidtyrosine phosphorylation of neuronal proteins including tau and focaladhesion kinase in response to amyloid-beta peptide exposure:involvement of Src family protein kinases. J Neurosci,2002,22:10-20.
[75] Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX. O-GlcN Acylationregulates phosphorylation of tau: A mechanism involved in Alzheimer'sdisease. Proc Natl Acad Sci USA,2004,101(29):10804-10809.
[76] Lefebvre T, Ferreira S, Dupont-Wallois L, Bussiere T, Dupire MJ,Delacourte A, Michalski JC, Caillet-Boudin ML. Evidence of a balancebetween phosphorylation and O-GlcNAc glycosylation of tau proteins-Arole in nuclear localization. Biochim Biophys Acta,2003,1619(2):167-176.
[77] Hershko A and Ciechanover A. The ubiquitin system. Annu Rev Biochem,1998,67:425-479.
[78] Mayer A, Siegel NR, Schwartz AL, and Ciechanover A. Degradation ofproteins with acetylated amino termini by the ubiquitin system. Science,1989,244:1480-1483.
[79] Yan SD, Chen X, Schmidt AM, Brett J, Godman G, Zou YS, Scott CW,Caputo C, Frappier T, Smith MA, Perry G, Yen SH, and Stem D. Glycatedtau protein in Alzheimer disease: a mechanism for induction of oxidantstress. Proc Natl Acad Sci USA,1994,91:7787-7791.
[80] Ledesma MD, Bonay P, and Avila J. Tau protein from Alzheimer’s diseasepatients is glycated at its tubulin-binding domain. J Neurochem,1995,65:1658-1664.
[81] Smith MA, Sayre LM, Monnier VM, and Perry G. Radical AGEing inAlzheimer’s disease. Trends Neurosci,1995,18:172-176.
[82] Wischik CM, Lai RYK, and Harrington CR. Modelling prion-likeprocessing of tau protein in Alzheimer’s disease for pharmaceuticaldevelopment. In: Brain Microtubule Associated, edited by Avila J, BrandtR, and Kosik KS. Chur, Switzerland: Harwood Academic,1997, p:185-241.
[83] Montejo de Garcini E, Serrano L, and Avila J. Self-assembly ofmicrotubule associated protein tau into flaments resembling those found inAlzheimer disease. Biochem Biophys Res Commun,1986,141:790-796.
[84] Frame S, Cohen P, and Biondi RM. A common phosphate binding siteexplains the unique substrate specifcity of GSK3and its inactivation byphosphorylation. Mol Cell,2001,7:1321-1327.
[85] Cho JH and Johnson GV. Glycogen synthase kinase3beta (GSK3beta)phosphorylates tau at both primed and unprimed sites: differential impacton microtubule binding. J Biol Chem,2002,278:187-193.
[86] Gong CX, Grundke-Iqbal I, and Iqbal K. Dephosphorylation ofAlzheimer’s disease abnormally phosphorylated tau by proteinphosphatase-2A. Neuroscience,1994,61:765-772.
[87] Gong CX, Singh TJ, Grundke-Iqbal I, and Iqbal K. Alzheimer’s diseaseabnormally phosphorylated tau is dephosphorylated by proteinphosphatase-2B (calcineurin). J Neurochem,1994,62:803-806.
[88] Goedert M, Jakes R, Qi Z, Wang JH, and Cohen P. Protein phosphatase2Ais the major enzyme in brain that dephosphorylates tau proteinphosphorylated by proline-directed protein kinases or cyclicAMP-dependent protein kinase. J Neurochem,1995,65:2804-2807.
[89] Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, and Iqbal K.Phosphorylation of microtubule-associated protein tau are regulated byprotein phosphatase2A in mammalian brain. Implications forneurofbrillary degeneration in Alzheimer’s disease. J Biol Chem,2000,275:5535-5544.
[90] Hyman BT, Augustinack JC, Ingelsson M. Transcriptional andconformational changes of the tau molecule in Alzheimer’s disease.Biochim. Biophys. Acta.,2005,1739:150-157.
[91] Lee, V. M. Goedert, M. Trojanowski, J. Q. Neurodegenerative tauopathies.Annu. Rev. Neurosci.,2001,24:1121-1159.
[92] Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G,Pickering-Brown S, Duff K, Hutton M.5' splice site mutations in tauassociated with the inherited dementia FTDP-17affect a stem-loopstructure that regulates alternative splicing of exon10. J. Biol. Chem.,1999,274:15134-15143.
[93] Varani L, Hasegawa M, Spillantini MG, Smith MJ, Murrell JR, Ghetti B,Klug A, Goedert M, Varani G. Structure of tau exon10splicing regulatoryelement RNA and destabilization by mutations of frontotemporal dementiaand parkinsonism linked to chromosome17. Proc. Natl. Acad. Sci. U. S. A.,1999,96:8229-8234.
[94] Conrad C, Zhu J, Conrad C, Schoenfeld D, Fang Z, Ingelsson M, Stamm S,Church G, Hyman BT. Single molecule profling of tau gene expression inAlzheimer’s disease. J. Neurochem.,2007,103:1228–1236.
[95] Sergeant N, David JP, Lefranc D, Vermersch P, Wattez A, Delacourte A.Different distribution of phosphorylated tau protein isoforms inAlzheimer’s and Pick’s diseases. FEBS Lett,1997,412:578-582.
[96] Stoothoff, W.H. and Johnson, G.V. Tau phosphorylation: physiological andpathological consequences. Biochim. Biophys. Acta.,2005,1739:280-297.
[97] Drewes G, Trinczek B, Illenberger S, Biernat J, Schmitt-Ulms G, MeyerHE, Mandelkow EM, Mandelkow E. Microtubule-associatedprotein/microtubule affnity-regulating kinase (p110mark). A novel proteinkinase that regulates tau-microtubule interactions and dynamic instabilityby phosphorylation at the Alzheimer-specifc site serine262. J. Biol.Chem.,1995,270:7679-7688.
[98] Song, J.S. and Yang, S.D. Tau protein kinase I/GSK-3b/kinase FA inheparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369,and Ser400sites phosphorylated in Alzheimer disease brain. J. ProteinChem.,1995,14:95-105.
[99] Delacourte, A. Tau, a biological marker of neurodegenerative disease. InDementias,2008,89:161-172.
[100] Eidenmüller J, Fath T, Maas T, Pool M, Sontag E, Brandt R.Phosphorylation-mimicking glutamate clusters in the proline-rich regionare suffcient to simulate the functional defciencies ofhyperphosphorylated tau protein. Biochem. J.,2001,357:759-767.
[101] Fath T, Eidenmüller J, Brandt R. Tau-mediated cytotoxicity in apseudohyperphosphorylation model of Alzheimer’s disease. J. Neurosci.,2002,22:9733-9741.
[102] Léger J, Kempf M, Lee G, Brandt R. Conversion of serine to aspartateimitates phosphorylation-induced changes in the structure and function ofmicrotubule-associated protein tau. J. Biol. Chem.,1997,272:8441-8446.
[103] Kuret J, Congdon EE, Li G, Yin H, Yu X, Zhong Q. Evaluating triggers andenhancers of tau fbrillization. Microsc. Res. Tech.,2005,67:141-155.
[104] Alonso Adel C, Li B, Grundke-Iqbal I, Iqbal K. Polymerization ofhyperphosphorylated tau into flaments eliminates its inhibitory activity.Proc. Natl. Acad. Sci. U. S. A.,2006,103:8864-8869.
[105] Chun, W. and Johnson, G.V. Activation of glycogen synthase kinase3bpromotes the intermolecular association of tau. The use of fuorescenceresonance energy transfer microscopy. J. Biol. Chem.,2007,282:23410-23417.
[106] Rohn TT, Vyas V, Hernandez-Estrada T, Nichol KE, Christie LA, Head E.Lack of pathology in a triple transgenic mouse model of Alzheimer’sdisease after overexpression of the anti-apoptotic protein Bcl-2. J.Neurosci.,2008,28:3051-3059.
[107] Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E. Clogging ofaxons by tau, inhibition of axonal traffc and starvation of synapses.Neurobiol Aging,2003,24:1079-1085.
[108] Kempf M, Clement A, Faissner A, Lee G, Brandt R. Tau binds to the distalaxon early in development of polarity in a microtubule-andmicroflament-dependent manner. J. Neurosci.,1996,16:5583-5592.
[109] Ferrari A, Hoerndli F, Baechi T, Nitsch RM, G tz J. beta-Amyloid inducespaired helical flament-like tau flaments in tissue culture. J. Biol. Chem.,2003,278:40162-40168.
[110] Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL,Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI,Cryns VL. Caspase cleavage of tau: linking amyloid and neurofbrillarytangles in Alzheimer’s disease. Proc. Natl. Acad. Sci. USA.,2003,100:10032-10037.
[111] Rapoport, M. Dawson, H. N. Binder, L. I. Vitek, M. P. Ferreira, A. Tau isessential to beta-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci.USA.,2002,99:6364-6369.
[112] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM. Abetaimmunotherapy leads to clearance of early, but not late,hyperphosphorylated tau aggregates via the proteasome. Neuron,2004,43:321-332.
[113] Woodgett, J.R.. A common denominator linking glycogen metabolism,nuclear oncogenes and development. TIBS,1991,16:177-181.
[114] Eldar-Finkelman, H., Argast, G.M., Foord, O., Fischer, E.H., Krebs, E.G..Expression and characterization of glycogen synthase kinase-3mutants andtheir effect on glycogen synthase activity in intact cells. Proc. Natl. Acad.Sci. USA,1996,93:10228-10233.
[115] Woodgett, J.R.. Molecular cloning and expression of glycogen synthasekinase-3: Factor A. EMBO J,1990,9:2431-2438.
[116] Pei, J.J., Tanaka, T., Tung, Y.C., Braak, E., Iqbal, K., Grundke-Iqbal, I..Distribution, levels, and activity of glycogen synthase kinase-3in theAlzheimer disease brain. J. Neuropathol. Exp. Neurol.,1997,56:70-78.
[117] Takahashi, M., Tomizawa, K., Kato, R., Sato, K., Uchida, T., Fujita, S.C.,Imahori, K.. Localization and developmental changes of t protein kinase I:glycogen synthase kinase-3b in rat brain. J. Neurochem.,1994,63:245-255.
[118] Grimes C. A. and Jope R. S. The multifaceted roles of glycogen synthasekinase3beta in cellular signaling. Prog. Neurobiol.,2001,65:391-426.
[119] Doble B. W. and Woodgett J. R. GSK-3: tricks of the trade for amulti-tasking kinase. J. Cell Sci.,2003,116:1175-1186.
[120] Hughes K., Nikolakaki E., Plyte E. S., Totty N. F. and Woodgett J. R.Modulation of the glycogen synthase kinase-3family by tyrosinephosphorylation. EMBO J,1993,12:803-808.
[121] Cook D., Fry J. M., Hughes K., Sumathipala R., Woodgett J. R. and Dale T.C. Wingless inactivates glycogen synthase kinase-3via an intracellularsignalling pathway which involves a protein kinase C. EMBO J,1996,15:4526-4536.
[122] Yost C., Farr3rd H. G., Pierce B. S., Ferkey M. D., Chen M. M. andKimelman D. GBP, an inhibitor of GSK-3, is implicated in Xenopusdevelopment and oncogenesis. Cell,1998,93:1031-1041.
[123] Hart J. M., Santos de los R., Albert N. I., Rubinfeld B. and Polakis P.Downregulation of beta-catenin by human Axin and its association withthe APC tumor suppressor B., beta-catenin and GSK3beta. Curr. Biol.,1998,8:573-581.
[124] Noort van M., Meeldijk J., Zee van der R., Destree O. and Clevers H. Wntsignaling controls the phosphorylation status of beta-catenin. J. Biol.Chem.,2002,277:17901-17905.
[125] M. P. Mattson. Cellular actions of beta-amyloid precursor protein and itssoluble and fibrillogenic derivatives. Physiol. Rev.,1997,77:1081-1132.
[126] Pangalos N. M., Jacobsen S. J. and Reinhart P. H. Disease modifyingstrategies for the treatment of Alzheimer’s disease targeted at modulatinglevels of the beta-amyloid peptide. Biochem. Soc. Trans.,2005,33:553-558.
[127] Kim HS, Kim EM, Lee JP, Park CH, Kim S, Seo JH, Chang KA, Yu E,Jeong SJ, Chong YH, Suh YH. C-terminal fragments of amyloid precursorprotein exert neurotoxicity by inducing glycogen synthase kinase-3betaexpression. FASEB J,2003,17:1951-1953.
[128] Rapoport M., Dawson N. H., Binder I. L., Vitek M. P. and Ferreira A. Tauis essential to beta-amyloid-induced neurotoxicity. Proc. Natl. Acad. Sci.USA,2002,99:6364-6369.
[129] Su Y, Ryder J, Li B, Wu X, Fox N, Solenberg P, Brune K, Paul S, Zhou Y,Liu F, Ni B. Lithium, a common drug for bipolar disorder treatment,regulates amyloid-beta precursor protein processing. Biochemistry,2004,43:6899-6908.
[130] Phiel J. C., Wilson A. C., Lee V. M. and Klein P. S. GSK-3alpha regulatesproduction of Alzheimer’s disease amyloid-beta peptides. Nature,2003,423:435-439.
[131] Xia W., Zhang J., Perez R., Koo E. H. and Selkoe D. J. Interaction betweenamyloid precursor protein and presenilins in mammalian cells:implications for the pathogenesis of Alzheimer disease. Proc. Natl. Acad.Sci. USA,1997,94:8208-8213.
[132] Weihl C. C., Ghadge D. G., Kennedy G. S., Hay N., Miller R. J. and RoosR. P. Mutant presenilin-1induces apoptosis and downregulates Akt/PKB. J.Neurosci.,1999,19:5360-5369.
[133] Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K,Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B.Presenilin1associates with glycogen synthase kinase-3beta and itssubstrate tau. Proc. Natl. Acad. Sci. USA,1998,95:9637-9641.
[134] Kirschenbaum F., Hsu C. S., Cordell B. and McCarthy J. V. Substitution ofa glycogen synthase kinase-3beta phosphorylation site in presenilin1separates presenilin function from beta-catenin signaling. J. Biol. Chem.,2001,276:7366-7375.
[135] Kirschenbaum F., Hsu C. S., Cordell B. and McCarthy J. V. Glycogensynthase kinase-3beta regulates presenilin1C-terminal fragment levels. J.Biol. Chem.,2001,276:30701-30707.
[136] Flaherty B. D., Soria P. J., Tomasiewicz H. G. and Wood J. G.Phosphorylation of human tau protein by microtubule associated kinases:GSK3beta and cdk5are key participants. J. Neurosci. Res.,2000,62:463-472.
[137] Ishiguro K, Omori A, Takamatsu M, Sato K, Arioka M, Uchida T, ImahoriK. Phosphorylation sites on tau by tau protein kinase I, a bovine derivedkinase generating an epitope of paired helical filaments. Neurosci. Lett.,1992,148:202-206.
[138] Imahori K, Hoshi M, Ishiguro K, Sato K, Takahashi M, Shiurba R,Yamaguchi H, Takashima A, Uchida T. Possible role of tau protein kinasesin pathogenesis of Alzheimer’s disease. Neurobiology Aging,1998,19:S93-S98.
[139] Pap M. and Cooper G. M. Role of glycogen synthase kinase-3in thephosphatidylinositol3-kinase/Akt cell survival pathway. J. Biol. Chem.,1998,273:19929-19932.
[140] Karelle Leroy, Jean-Pierre Brion. Developmental expression andlocalization of glycogen synthase kinase-3b in rat brain. Journal ofChemical Neuroanatomy,1999,16:279-293.
[141] V. Janssens, J.Goris. Protein phosphatase2A: a highly regulated family ofserine/threonine phosphatases implicated in cell growth and signaling.Biochem. J.,2001,53:417-439.
[142] P. T. W. Cohen, N. D. Brewis, V. Hughes, D. J. Mann. Proteinserine/threonine phosphatases; an expanding family. FEBS Lett,1990,268:355-359.
[143] P. Agostinis, J. Goris, L.A. Pinna, F.M. archiori, J.W. Perich, H.E.Meyer, W.Merlevede. Synthetic peptides as model substrates for the study of thespecifcity of the polycation-stimulated protein phosphatases. Eur. J.Biochem.,1990,189:235-241.
[144] F. Liu, I. Grundke-Iqbal, K. Iqbal, C.X. Gong. Contributions of proteinphosphatases PP1, PP2A, PP2B and PP5to the regulation of tauphosphorylation. Eur. J. Neurosci.,2005,22:1942-1950.
[145] E. Sontag, V. Nunbhakdi-Craig, J.M. Sontag, R. Diaz-Arrastia, E.Ogris, S.Dayal, S.R. Lentz, E. Arning, T. Bottiglieri. Protein phosphatase2Amethyltransferase links homocysteine metabolism with tau and amyloidprecursor protein regulation. J. Neurosci.,2007,27:2751-2759.
[146] S. Kins, A. Crameri, D. R. Evans, B. A. Hemmings, R. M. Nitsch, J. Gotz.Reduced protein phosphatase2A activity induces hyperphosphorylationand altered compartmentalization of tau in transgenicmice. J. Biol. Chem.,2001,276:38193-38200.
[147] S. E. Gandy, G. L. Caporaso, J. D. Buxbaum, S. O. de Cruz, K. Iverfeldt, C.Nordstedt, T. Suzuki, A. J. Czernik, A. C. Nairn, P. Greengard. Proteinphosphorylation regulates relative utilization of processing pathways forAlzheimer beta/A4amyloid precursor protein. Ann. N.Y. Acad. Sci.,1993,695:117-121.
[148] J.D. Buxbaum, E.H. Koo, P. Greengard. Protein phosphorylation inhibitsproduction of Alzheimer amyloid beta/A4peptide. Proc. Natl. Acad. Sci.U.S.A.,1993,90:9195-9198.
[149] T. Arendt, M. Holzer, R. Fruth, M.K. Bruckner, U. Gartner.Phosphorylation of tau, Abeta formation, and apoptosis after in vivoinhibition of PP-1and PP-2A. Neurobiol. Aging,1998,19:3-13.
[150] K. Ando, K. I. Iijima, J. I. Elliott, Y. Kirino, T. Suzuki. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein withFe65affects the production of beta-amyloid. J. Biol. Chem.,2001,276:40353-40361.
[151] V. Vogelsberg-Ragaglia, T. Schuck, J.Q. Trojanowski, V.M. Lee. PP2AmRNA expression is quantitatively decreased in Alzheimer’s diseasehippocampus. Exp. Neurol.,2001,168:402-412.
[152] E. Sontag, A. Luangpirom, C. Hladik, I.Mudrak, E. Ogris, S. Speciale,C.L.White III. Altered expression levels of the protein phosphatase2AABalphaC enzyme are associated with Alzheimer disease pathology. J.Neuropathol. Exp. Neurol.,2004,63:287-301.
[153] R. Liu, X.W. Zhou, H. Tanila, C. Bjorkdahl, J.Z. Wang, Z.Z. Guan, Y. Cao,J.A. Gustafsson, B. Winblad, J.J. Pei. Phosphorylated PP2A (tyrosine307)is associated with Alzheimer neurofbrillary pathology. J. Cell. Mol. Med.,2008,12:241-257.
[154] E. Sontag, V. Nunbhakdi-Craig, G. Lee, G.S. Bloom, M.C. Mumby.Regulation of the phosphorylation state andmicrotubule-binding activity ofTau by protein phosphatase2A. Neuron,1996,17:1201-1207.
[155] M. Li, H. Guo, Z. Damuni. Purifcation and characterization of two potentheat-stable protein inhibitors of protein phosphatase2A from bovinekidney. Biochemistry,1995,34:1988-1996.
[156] S. Chen, B. Li, I. Grundke-Iqbal, K. Iqbal. I1PP2A affects tauphosphorylation via associationwith the catalytic subunit of proteinphosphatase2A. J. Biol. Chem.,2008,283:10513-10521.
[157] H. Tanimukai, I. Grundke-Iqbal, K. Iqbal. Up-regulation of inhibitors ofprotein phosphatase-2A in Alzheimer’s disease. Am. J. Pathol.,2005,166:1761-1771.
[158] E. Sontag. Protein phosphatase2A: the Trojan Horse of cellular signaling.Cell. Signal.,2001,13:7-16.
[159] E. Sontag, C. Hladik, L. Montgomery, A. Luangpirom, I. Mudrak, E. Ogris,C.L. White III. Downregulation of protein phosphatase2A carboxylmethylation and methyltransferase may contribute to Alzheimer diseasepathogenesis. J. Neuropathol. Exp. Neurol.,2004,63:1080-1091.
[160] X.W. Zhou, J.A. Gustafsson, H. Tanila, C. Bjorkdahl, R. Liu, B. Winblad,J.J. Pei. Tau hyperphosphorylation correlates with reduced methylation ofprotein phosphatase2A. Neurobiol. Dis.,2008,31:386-394.
[161] H. Guo, S.A. Reddy, Z. Damuni. Purifcation and characterization of anautophosphorylation-activated protein serine threonine kinase thatphosphorylates and inactivates protein phosphatase2A. J. Biol. Chem.,1993,268:11193-11198.
[162] Wang L, Zhang Y, Wang Z, Li S, Min G, Wang L, Chen J, Cheng J, Wu Y.Inhibitory effect of ginsenoside-Rd on carrageenan-induced inflammationin rats. Can J Physiol Pharmacol,2012,90(2):229-36.
[163] Yang XL, Guo TK, Wang YH, Huang YH, Liu X, Wang XX, Li W, ZhaoX, Wang LP, Yan S, Wu D, Wu YJ. Ginsenoside Rd attenuates theinflammatory response via modulating p38and JNK signaling pathways inrats with TNBS-induced relapsing colitis. Int Immunopharmacol,2012,12(2):408-14.
[164] Lin WM, Zhang YM, Moldzio R, Rausch WD. Ginsenoside Rd attenuatesneuroinflammation of dopaminergic cells in culture. J Neural TransmSuppl,2007,72:105-12.
[165] Li SY, Wang XG, Ma MM, Liu Y, Du YH, Lv XF, Zhou JG, TangYB, Guan YY. Ginsenoside-Rd potentiates apoptosis induced by hydrogenperoxide in basilar artery smooth muscle cells through the mitochondrialpathway. Apoptosis,2012,17(2):113-20.
[166] Ye R, Zhang X, Kong X, Han J, Yang Q, Zhang Y, Chen Y, Li P, Liu J, ShiM, Xiong L, Zhao G. Ginsenoside Rd attenuates mitochondrial dysfunctionand sequential apoptosis after transient focal ischemia. Neuroscience,2011,78:169-80.
[167] Li XY, Liang J, Tang YB, Zhou JG, Guan YY. Ginsenoside Rd preventsglutamate-induced apoptosis in rat cortical neurons. Clin Exp PharmacolPhysiol,2010,37(2):199-204.
[168] Tamura T, Cui X, Sakaguchi N, Akashi M. Ginsenoside Rd prevents andrescues rat intestinal epithelial cells from irradiation-induced apoptosis.Food Chem Toxicol,2008,46(9):3080-9.
[169] Yang ZG, Sun HX, Ye YP. Ginsenoside Rd from Panax notoginseng iscytotoxic towards HeLa cancer cells and induces apoptosis. ChemBiodivers,2006,3(2):187-97.
[170] Zhang Y, Zhou L, Zhang X, Bai J, Shi M, Zhao G. Ginsenoside-Rd attenuates TRPM7and ASIC1a but promotes ASIC2a expression in ratsafter focal cerebral ischemia. Neurol Sci,2012, Jan10.
[171] Zhang C, Du F, Shi M, Ye R, Cheng H, Han J, Ma L, Cao R, Rao
[172] Z, Zhao G. Ginsenoside Rd protects neurons against glutamate-inducedexcitotoxicity by inhibiting Ca2+influx. Cell Mol Neurobiol,2012,32(1):121-8.
[173] Wang L, Zhang Y, Chen J, Li S, Wang Y, Hu L, Wang L, Wu Y.Immunosuppressive Effects of Ginsenoside-Rd on Skin Allograft Rejectionin Rats. J Surg Res,2011, Jul21.
[174] Li L, Liu J, Yan X, Qin K, Shi M, Lin T, Zhu Y, Kang T, Zhao G. Protectiveeffects of ginsenoside Rd against okadaic acid-induced neurotoxicity invivo and in vitro. J Ethnopharmacol,2011, Oct31,138(1):135-41.
[175] Liu X, Xia J, Wang L, Song Y, Yang J, Yan Y, Ren H, Zhao G. Efficacy andsafety of ginsenoside-Rd for acute ischaemic stroke: a randomized,double-blind, placebo-controlled, phase II multicenter trial. Eur JNeurol,2009,16(5):569-75.
[176] Liu X, Wang L, Wen A, Yang J, Yan Y, Song Y, Liu X, Ren H, Wu Y, LiZ, Chen W, Xu Y, Li L, Xia J, Zhao G. Ginsenoside-Rd improves outcomeof acute ischaemic stroke-a randomized, double-blind, placebo-controlled,multicenter trial. Eur J Neurol,2012, Jan10.
[177] Butterfield DA, Howard B, Yatin S, Koppal T, Drake J, Hensley K,Aksenov M, Aksenova M, Subramaniam R, Varadarajan S, Harris-WhiteME, Pedigo NW Jr, Carney JM. Elevated oxidative stress in models ofnormal brain aging and Alzheimer’s disease. Life Sci,1999,65(18):1883-1892.
[178] Choi SS, Lee JK, Han EJ, Han KJ, Lee HK, Lee J, Suh HW. Effect ofginsenoside Rd on nitric oxide system induced by lipopolysaccharide plusTNF-alpha in C6rat glioma cells. Arch Pharm Res,2003,26(5):375-82.
[179] Goedert, M. and Spillantini, M.G. A century of Alzheimer’s disease.Science,2006,314:777-781.
[180] Ferrer I, Gomez-Isla T, Puig B, Freixes M, Ribe E, Dalfo E, Avila J.Current advances on different kinases involved in tau phosphorylation, andimplications in Alzheimer's disease and tauopathies. Curr Alzheimer Res,2005,2(1):3-18.
[181] Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH. Glycogensynthase kinase-3induces Alzheimer’s disease-like phosphorylation of tau:generation of paired helical filament epitopes and neuronal localisation ofthe kinase. Neurosci. Lett.,1992,147:58-62.
[182] Drewes G, Mandelkow EM, Baumann K, Goris J, Merlevede W,Mandelkow E. Dephosphorylation of tau protein and Alzheimer pairedhelical filaments by calcineurin and phosphatase-2A. FEBS Lett,1993,336:425-432.
[183] Liu F, Liang Z, Shi J, Yin D, El-Akkad E, Grundke-Iqbal I, Iqbal K, GongCX. PKA modulates GSK-3beta-and cdk5-catalyzed phosphorylation oftau in site-and kinase-specific manners. FEBS Lett,2006,580(26):6269-74.
[184] J. Q. Trojanowski, V. M. Lee. Phosphorylation of paired helical filamenttau in Alzheimer’s disease neurofibrillary lesions: focusing onphosphatases. FASEB J,1995,9:1570-1576.
[185] Kazuo, T., Paul, J. S., Yasumasa, T., Hiroyuki, K., Donna, V. E., Jon, C.,Yalamanchili, G., Francis, J. S..“Okadaic acid, a cytotoxic polyether fromtwo marine sponges of the genus Halichondria”. Journal of the AmericanChemical Society,1981,103:2469-2471.
[186] Alphonse, G., Xavier, C., Julien, G., Frédéric, D., Véronique, H., Maria, P.R., Aarne, F., Angelita, R..“Serine/threonine protein phosphatases PP1andPP2Aare key players in apoptosis”. Biochimie,2003,85:721-726.