Tau蛋白异常导致阿尔茨海默病等神经退行性Tau蛋白病的机制与研究进展

摘要/Abstract

摘要： Tau蛋白是神经细胞特有的微管相关蛋白，其基本功能是促进微管蛋白组装成微管，维持正常神经轴突运输及微管稳定性。既往基于尸检发现脑部神经纤维缠结（neurofibrillary tangles，NFTs) 与神经元死亡、细胞形态异常及凋亡之间呈良好的平行关系，因而NFTs被认为是引起神经退行性Tau蛋白病的重要原因，并认为与Tau蛋白的过磷酸化有关；但新近发现单纯Tau蛋白磷酸化并不足以形成NFTs，还必须有其他诸如糖基化、脯氨酸异构化、泛素化等翻译后修饰机制的协同，其他如Tau蛋白基因突变、自噬的抑制等也与NFTs形成有关。尤其是最近采用转基因活体动物和多光子影像技术的研究显示，NFTs可能只是疾病晚期的临床表现，而可溶性的Tau蛋白才是启动下游病理反应的关键因素。更为引人注目的是，抑制Tau蛋白还可以阻止Aβ引起的神经细胞凋亡、减轻记忆损害，换言之即Aβ的毒性是Tau蛋白依赖性的。随着近期对Tau蛋白异常介导神经退行性Tau蛋白病及其机制的新认识以及以Aβ为靶点的药物研发宣告失败，人们愈来愈重视以Tau 为靶点的药物开发。

关键词: Tau蛋白, A&, beta, 神经退行性变, 阿尔茨海默病, 药物靶点

Abstract: Tau, as a neuronally specific microtubule associated protein, plays a key role in promoting tubulin associated microtubule assembly, sustaining normal neuron axonal transport and stabilizing microtubule structure. Previous studies in autopsy revealed a tangible parallel relationship of brain neurofibrillary tangles (NFTs) to neurodegeneration, cell dysmorphology and apoptosis, thus leading to the consensus of NFTs being the major pathogenic factor in neurodegenerative taupathies, which are related to tau protein hyperphosphorylation. However, recent discoveries showed that Tau phosphorylation alone is insufficient for the formation of NFTs; other post-translational modifications such as glycosylation, proline isomerization, ubiquitination, as well as tau gene mutation and autophagy inhibition, are also required. In particular, recent researches using transgenic animals and multiphoton imaging technology indicated that NFTs seem to be just one clinical manifestation at the advanced stage of this disease, whereas soluble Tau protein plays an important role in initiating downstream pathological processes. Remarkably, suppression of Tau prohibited Aβ induced neuronal apoptosis and reduced memory impairment, suggesting that Aβ toxicity is Tau protein dependent. Along with the recent new light shed on the Tau abnormality induced neurodegenerative taupathies and its mechanism, Aβ as a drug target proved to be a failure in the field of drug discovery. As a result increasing attention has been given to tau targeted drug development.

Key words: tau protein, A&, beta, neurodegeneration, Alzheimer 's disease, therapeutic target

中图分类号:

R964

李礼轩, 李晓辉. Tau蛋白异常导致阿尔茨海默病等神经退行性Tau蛋白病的机制与研究进展[J]. 神经药理学报, 2011, 1(5): 34-39.

LI Li-xuan, LI Xiao-hui. The Mechanisms and Research Progress of Tau Abnormality Leading to AD Related Neurodegenerative Taupathies[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(5): 34-39.

参考文献

1 Tara L Spires-Jones，Katherine J Kopeikina，Robert M Koffie，et al. Are tangles as toxic as they look? [J]. J Mol Neurosci, 2011, 45(3):438-444.

2 Ludovic Martina, Xenia Latypovaa, Faraj Terroa. Post-translational modifications of tau protein: Implications for Alzheimer’s disease[J]. Nerrochem Int, 2011, 58(4):458-471.

3 Alix de Calignon, Leora M Fox, Rose Pitstick, et al. Caspsse activation precedes and leads to tangles[J]. Nature, 2010, 464(7292):1201-1204.

4 Marx J. Alzheimer's disease. a new take on tau[J]. Science, 2007, 316(5830):1416-1417.

5 Chen Shu-fen, Kirk Townsend, Terry E Goldberg, et al. MAPT isoforms: differential transcriptional profiles related to 3R and 4R splice variants[J]. J Alzheimers Dis, 2010, 22(4):1313-1329.

6 Julien Lefèvre, Konstantin G Chernov, Vandana Joshi, et al.The C terminus of tubulin, a versatile partner for cationic molecules: binding of Tau, polyamines, and calcium[J]. J Biol Chem, 2011, 286(4):3065-3078.

7 Scott A Yuzwa, David J Vocadlo. O-GlcNAc modification and the tauopathies: insights from chemical biology [J]. Curr Alzheimer Res, 2009, 6(5):451-454.

8 Natalia Crespo-Biel, Clara Theunis, Fred Van Leuven. Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease[J]. Int J Alzheimers Dis, 2012, 2012:251426.

9 Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by taus amino-terminal projection domain[J]. J Cell Biol, 1995, 131(5):1327-1340.

10 Thorsten Maas, Jochen Eidenmüller, Roland Brandt. Interaction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments[J]. J Biol Chem, 2000, 275(21):15733-15740.

11 Tudor A Fulga, Ilan Elson-Schwab, Vikram Khurana, et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo[J]. Nat Cell Biol, 2007, 9(2):139-148.

12 Xu Shao-hua, Kurt R Brunden, John Q Trojanowski, et al. Characterization of tau fibrillization in vitro[J]. Alzheimers Dement, 2010, 6(2):110-117.

13 Georg Künze, Patrick Barré, Holger A Scheidt, et al. Binding of the three-repeat domain of tau to phospholipid membranes induces an aggregated-like state of the protein[J]. Biochim Biophys Acta, 2012, 1818(9):2302-2313.

14 Michel Goedert, Ross Jakes. Mutations causing neurodegenerative tauopathies[J]. Biochim Biophys Acta, 2005, 1739(2-3):240-250.

15 So-Young Park, Adriana Ferreira . The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration[J]. J Neurosci, 2005, 25(22):5365-5375.

16 T.Chris Gamblin, Feng Chen, Angara Zambrano, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease[J]. Proc Natl Acad Sci USA, 2003, 100(17):10032-10037.

17 Sing-In Kim, Won-Ki Lee, Sang-Soo Kang, et al. Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau[J]. J Physiol Pharmacol，2011，15(2)：107-114.

18 Tudro A Fulga, Ilan Elson-Schwab, Vikram Khurana, et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo[J]. Nat Cell Biol, 2007, 9(2):139-148.

19 Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease[J]. Neurology, 1992, 42(3 Pt 1):631-639.

20 Dickson DW, Crystal HA, Mattiace LA, et al. Identification of normal and pathological aging in prospectively studied nondemented elderly humans[J]. Neurobiol Aging, 1992, 13(1):179-189.

21 Mike Hutton, Corinne L Lendon, Patrizia Rizzu, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17[J]. Nature, 1998, 393(6686):702-705.

22 Maria G Spillantini, Jill R Murrell, Michel Goedert, et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia[J]. Proc Natl Acad Sci USA, 1998, 95(13):7737-7741.

23 Anatoly Nikolaev, Todd McLaughlin, Dennis D O'Leary, et al. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases[J]. Nature, 2009, 457(7232):981-989.

24 Lars M Ittner, Yazi D Ke, Fabien Delerue, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models[J]. Cell, 2010, 142(3):387-397.

25 Lee Gloria, S.Todd Newman, David L Gard, et al. Tau interacts with src-family non-receptor tyrosine kinases[J]. J Cell Sci, 1998, 111(Pt 21):3167-3177.

26 Kiran Bhaskar, Yen Shu-Hui, Lee Gloria. Disease-related modifications in tau affect the interaction between Fyn and Tau[J]. J Biol Chem, 2005, 280(42):35119-35125.

27 Götz J, Streffer JR, David D, et al. Transgenic animal models of Alzheimer's disease and related disorders: histopathology, behavior and therapy[J]. Mol Psychiatry, 2004, 9(7):664-683.

28 Roberson ED, Scearce-Levie K, Palop JJ, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model[J]. Science, 2007, 316(5825):750-754.

29 David J Irwin, Todd J Cohen, Murray Grossman, et al. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies[J]. Brain, 2012, 135(Pt 3):807-818.

30 David E Hurtado, Laura Molina-Porcel, Michiyo Iba, et al. A{beta} accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model[J]. Am J Pathol, 2010, 177(4):1977-1988.

31 Lars M Ittner, Jurgen Götz. Amyloid-β and tau--a toxic pas de deux in Alzheimer's disease[J]. Nat Rev Neurosci, 2011, 12(2):65-72.

32 Kurt R Brunden, John Q Trojanowski, Virginia MY Lee. Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies[J]. Nat Rev Drug Discov, 2009, 8(10):783-793.

33 Gong Cheng-xin, Grundke-Iqbal Inge, Iqbal Khalid. Targeting tau protein in Alzheimer's disease[J]. Drugs Aging, 2010, 27(5):351-365.

34 Michael P Mazanetz, Peter M Fischer. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases[J]. Nat Rev Drug Discov, 2007, 6(6):464-479.

35 Rilee H Robeson, Travis Dunckley. High-content RNA interference assay: analysis of tau hyperphosphorylation as a generic paradigm[J]. Methods Mol Biol, 2011,700:221-238.

36 Hu Shu-xin, Aynun N Begum, Mychica R Jones, et al. GSK3 inhibitors show benefits in an Alzheimer's disease （AD） model of neurodegeneration but adverse effects in control animals[J]. Neurobiol Dis, 2009, 33(2):193-206.

37 Wischik CM, Edwards PC, Lai RY, et al. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines[J]. Proc Natl Acad Sci USA, 1996, 93(20):11213-11218.

38 Bruno Bulic, Marcus Pickhardt, Boris Schmidt, et al. Development of tau aggregation inhibitors for Alzheimer's disease[J]. Angew Chem Int Ed Engl, 2009, 48(10):1740-1752.

39 Nixon RA, Wegiel J, Kumar A, et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study[J]. J Neuropathol Exp Neurol, 2005, 64(2):113-122.

40 Susi Keck, Robert Nitsch, Tilman Grune, et al. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease[J]. Neurochem, 2003, 85(1):115-122.

41 Chad A Dickey, Judith Dunmore, Lu Bing-wei, et al. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS （MARK） sites[J]. FASEB J, 2006, 20(6):753-755.

42 Cai Zhi-you, Zhao Bin, Li Ke-shen, et al. Mammalian target of rapamycin: a valid therapeutic target through the autophagy pathway for Alzheimer's disease? [J]. J Neurosci Res, 2012, 90(6):1105-1118.

[1]	谢彬, 黄志源, 林多朵, 杨福龙, 谢奕彬. 针药结合干预阿尔茨海默病抑郁症状效果分析[J]. 神经药理学报, 2020, 10(5): 5-8.
[2]	赵雨薇, 甄艳杰, 戴月英, 沈丽霞. 槲皮素对阿尔茨海默症神经保护作用研究[J]. 神经药理学报, 2020, 10(5): 55-64.
[3]	海吉涛, 罗焕敏. 病原微生物与阿尔茨海默病相关性研究进展[J]. 神经药理学报, 2020, 10(4): 58-64.
[4]	杨旭华, 杜爽, 沈丽霞, 郝军荣. 阿尔茨海默病的药物治疗研究进展[J]. 神经药理学报, 2020, 10(3): 47-53.
[5]	甄艳杰, 郭童林, 赵雨薇, 沈丽霞. 植物雌激素介导线粒体途径对阿尔茨海默病神经保护作用的研究进展[J]. 神经药理学报, 2020, 10(1): 40-46.
[6]	杨琳，艾静. 脑源雌激素在阿尔茨海默病中的作用研究进展[J]. 神经药理学报, 2019, 9(5): 50-64.
[7]	魏珍珍，方晓艳，白明，苗明三. 基于星形胶质细胞的脑缺血损伤治疗研究进展[J]. 神经药理学报, 2019, 9(1): 36-43.
[8]	张帅，艾静. 谷氨酸功能异常与阿尔茨海默病[J]. 神经药理学报, 2018, 8(6): 9-20.
[9]	LIU Cai-hong，WU Xian，TANG Su-su，HONG Hao. Involvement of TGR5 in Aβ-Induced Neurotoxicity in Vivo*[J]. 神经药理学报, 2018, 8(4): 11-12.
[10]	SHEN li-xia1，LIU Liang-liang1，ZHANG Ming1，LIU Yang1，ZHANG Dan-shen 2. Research of Quercetin’s Estrogen-Like Action on Central Nervous System and Its Mechanisms*[J]. 神经药理学报, 2018, 8(4): 23-25.
[11]	WU Xian, LV Yang-ge, TANG Su-Su, HONG Hao. Involvement of TGR5 in Aβ-induced Neurotoxicity in Vivo[J]. 神经药理学报, 2018, 8(4): 53-54.
[12]	CHEN Fang，Arijit Ghosh，TANG Su-su，HONG Hao. Preventive Effect of Genetic Knockdown and Pharmacological Blockade of CysLT1R on Lipopolysaccharide（LPS）-induced Memory Deficit and Neurotoxicity in vivo[J]. 神经药理学报, 2018, 8(2): 29-29.
[13]	黄蕊，杨翠翠，张兰. 二苯乙烯苷对APP/PS1 双转基因小鼠学习记忆及突触可塑性的影响[J]. 神经药理学报, 2018, 8(2): 31-31.
[14]	刘双，李小慧，高健美，刘远贵，石京山，龚其海. 磷酸二酯酶5 抑制剂淫羊藿次苷II 通过BDNF/TrkB/CREB 信号通路减轻淀粉样蛋白25-35 片段诱导的大鼠学习记忆减退作用及机制研究[J]. 神经药理学报, 2018, 8(2): 44-44.
[15]	雷曦，王健辉，程肖蕊，张小锐，刘港，周文霞，张永祥. 基于快速老化模型小鼠SAMP8 的CA-30 抗阿尔茨海默病的作用研究[J]. 神经药理学报, 2018, 8(2): 50-50.