P301S突变tau转基因动物模型及其应用

doi:10.3969/j.issn.1674-5817.2017.06.015

摘要/Abstract

摘要： 微管相关蛋白tau在细胞内形成的神经纤维缠结是包括阿尔茨海默病(AD)、连锁于17号染色体伴帕金森综合征的额颞叶痴呆(FTDP-17)等在内的多种tau蛋白病(tauopathies)的主要病理表现之一。国内外学者在FTDP-17患者中发现了tau基因存在多个位点的突变,并以此为基础制作了多种tau转基因动物模型。其中P301S突变tau蛋白转基因小鼠模型在国内外的tau相关疾病研究中得到了广泛应用。本文综述了P301S突变tau转基因小鼠的病理表现及应用的新进展。

关键词: P301S突变, tau蛋白, 转基因小鼠, 阿尔茨海默病, tau蛋白病

Abstract: Microtubule associated protein tau is the major component of the intracellular filamentous deposits of several tauopathies, including Alzheimer’s disease, frontotemporal dementia with Parkinsonism linked to tau mutations on chromosome 17(FTDP-17) and so on. Mutations in Tau as the cause of FTDP-17 have been identified in recent years. And transgenic animal models based on tau mutations have been established. Among these models, P301S transgenic mouse has been widely used in the research on tauopathies. This article reviews the research progress in pathogenic manifestations of P301S mutant tau transgenic mice and their applications.

Key words: P301S mutation, Tau protein, Transgenic mouse, Alzheimer's disease, Tauopathy

中图分类号:

Q95-33

马登磊, 张兰. P301S突变tau转基因动物模型及其应用[J]. 实验动物与比较医学, 2017, 37(6): 491-496.

MA Deng-lei, ZHANG Lan. P301S Mutant Tau Transgenic Mouse and Their Applications[J]. Laboratory Animal and Comparative Medicine, 2017, 37(6): 491-496.

参考文献

[1] Nagy Z, Esiri MM, Jobst KA, et al.Relative roles of plaques and tangles in the dementia of Alzheimer’s disease: correlations using three sets of neuropathological criteria[J]. Dementia, 1995, 6(1):21-31.
[2] Murray ME, Lowe VJ, Graff-Radford NR, et al.Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer's disease spectrum[J]. Brain, 2015, 138(Pt 5):1370-1381.
[3] Gong CX, Grundke-Iqbal I, Iqbal K.Targeting tau protein in Alzheimer’s disease[J]. Drugs Aging, 2010, 27(5):351-365.
[4] Dujardin S, Colin M, Buée L.Invited review: Animal models of tauopathies and their implications for research/translation into the clinic[J]. Neuropathol Appl Neurobiol, 2015, 41(1):59-80.
[5] Noble W, Hanger DP, Gallo JM.Transgenic mouse models of tauopathy in drug discovery[J]. CNS Neurol Disord Drug Targets, 2010, 9(4):403-428.
[6] Weingarten MD, Lockwood AH, Hwo SY, et al.A protein factor essential for microtubule assembly[J]. Proc Natl Acad Sci U S A, 1975, 72(5):1858-1862.
[7] Dixit R, Ross JL, Goldman YE, et al.Differential regulation of dynein and kinesin motor proteins by tau[J]. Science, 2008, 319(5866):1086-1089.
[8] Liu CW, Lee G, Jay DG.Tau is required for neurite outgrowth and growth cone motility of chick sensory neurons[J]. Cell Motil Cytoskeleton, 1999, 43(3):232-242.
[9] Iqbal K, Liu F, Gong CX, et al.Mechanisms of tau-induced neurodegeneration[J]. Acta Neuropathol, 2009, 118(1):53-69.
[10] Iqbal K, Liu F, Gong CX.Tau and neurodegenerative disease: the story so far[J]. Nat Rev Neurol, 2016, 12(1):15-27.
[11] Li B, Chohan MO, Grundke-Iqbal I, et al.Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau[J]. Acta Neuropathol, 2007, 113(5):501-511.
[12] Hutton M, Lendon CL, Rizzu P, 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.
[13] Stenson PD, Mort M, Ball EV, et al.The human gene mutation database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine[J]. Hum Genet, 2014, 133(1):1-9.
[14] Hong M, Zhukareva V, Vogelsberg-Ragaglia V, et al.Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17[J]. Science, 1998, 282(5395): 1914-1917.
[15] Chang E, Kim S, Yin H, et al.Pathogenicmissense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps[J]. J Neurochem, 2008, 107(4):1113-1123.
[16] Alonso AD, Mederlyova A, Novak M, et al.Promotion of hyperphosphorylation by frontotemporal dementia tau mutations[J]. J Biol Chem, 2004, 279(33):34873-34881.
[17] Ludvigson AE, Luebke JI, Lewis J, et al.Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: a light and electron microscopy study[J]. Brain Struct Funct, 2011, 216(1):31-42.
[18] Yoshiyama Y, Higuchi M, Zhang B, et al.Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model[J]. Neuron, 2007, 53(3):337-351.
[19] Yamada K, Cirrito JR, Stewart FR, et al.In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice[J]. J Neurosci, 2011, 31(37):13110-13117.
[20] López-González I, Aso E, Carmona M, et al.Neuroinfla-mmatory gene regulation, mitochondrial function, oxidative stress, and brain lipid modifications with disease progression in tau P301S transgenic mice as a model of frontotemporal lobar degeneration-tau[J]. J Neuropathol Exp Neurol, 2015, 74(10):975-999.
[21] Dumont M, Stack C, Elipenahli C, et al.Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice[J]. FASEB J, 2011, 25(11):4063-4072.
[22] Boluda S, Iba M, Zhang B, et al.Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains[J]. Acta Neuropathol, 2015, 129(2):221-237.
[23] Crescenzi R, DeBrosse C, Nanga RP, et al. In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy[J]. Neuroimage, 2014, 101:185-192.
[24] Rossi G, Conconi D, Panzeri E, et al.Mutations in MAPT give rise to aneuploidy in animal models of tauopathy[J]. Neurogenetics, 2014, 15(1):31-40.
[25] Takeuchi H, Iba M, Inoue H, et al.P301S mutant human tau transgenic mice manifest early symptoms of human tauopathies with dementia and altered sensorimotor gating[J]. PLoS One, 2011, 6(6):e21050.
[26] Holmes BB, Furman JL, Mahan TE, et al.Proteopathic tau seeding predicts tauopathy in vivo[J]. Proc Natl Acad Sci USA, 2014, 111(41):E4376-4385.
[27] Iba M, Guo JL, McBride JD, et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy[J]. J Neurosci, 2013, 33(3):1024-1037.
[28] Kaufman SK, Sanders DW, Thomas TL, et al.Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo[J]. Neuron, 2016, 92(4):796-812.
[29] Cohen TJ, Guo JL, Hurtado DE, et al.The acetylation of tau inhibits its function and promotes pathological tau aggregation[J]. Nat Commun, 2011, 2:252.
[30] Min SW, Cho SH, Zhou Y, et al.Acetylation of tau inhibits its degradation and contributes to tauopathy[J]. Neuron, 2010, 67(6):953-966.
[31] Maeda J, Zhang MR, Okauchi T, et al.In vivo positron emission tomographic imaging of glial responses to amyloid-beta and tau pathologies in mouse models of Alzheimer’s disease and related disorders[J]. J Neurosci, 2011, 31(12):4720-4730.
[32] Ji B, Maeda J, Sawada M, et al.Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies[J]. J Neurosci, 2008, 28(47):12255-12267.
[33] Yoshiyama Y, Kojima A, Ishikawa C, et al.Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model[J]. J Alzheimers Dis, 2010, 22(1):295-306.
[34] Yoshiyama Y, Kojima A, Itoh K, et al.Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model[J]. Neurobiol Dis, 2012, 45(1):329-336.
[35] Yanamandra K, Kfoury N, Jiang H, et al.Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo[J]. Neuron, 2013, 80(2):402-414.
[36] Yanamandra K, Jiang H, Mahan TE, et al.Anti-tau antibody reduces insoluble tau and decreases brain atrophy[J]. Ann Clin Transl Neurol, 2015, 2(3):278-288.
[37] Sankaranarayanan S, Barten DM, Vana L, et al.Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models[J]. PLoS One, 2015, 10(5):e0125614.
[38] Richter M, Mewes A, Fritsch M, et al.Doubly phosphorylated peptide vaccines to protect transgenic P301S mice against Alzheimer's disease like tau aggregation[J]. Vaccines (Basel),2014, 2(3):601-623.
[39] Dumont M, Stack C, Elipenahli C, et al.Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice[J]. Hum Mol Genet, 2012, 21(23):5091-5105.
[40] Wagner J, Krauss S, Shi S, et al.Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies[J]. Acta Neuropathol, 2015, 130(5):619-631.
[41] Caccamo A, Magrì A, Medina DX, et al.mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies[J]. Aging Cell, 2013, 12(3):370-380.
[42] Jiang T, Yu JT, Zhu XC, et al.Temsirolimus attenuates tauopathy in vitro and in vivo by targeting tau hyperphosp-horylation and autophagic clearance[J]. Neuropharmacology, 2014, 85:121-130.
[43] Wang H, Wang R, Carrera I, et al.TFEB overexpression in the P301S model of tauopathy mitigates increased PHF1 levels and lipofuscin puncta and rescues memory deficits[J]. eNeuro, 2016, 3(2):1-18.
[44] DeVos SL, Miller RL, Schoch KM, et al. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy[J]. Sci Transl Med, 2017, 9(374):1-14.
[45] Brunden KR, Zhang B, Carroll J, et al.Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy[J]. J Neurosci, 2010, 30(41):13861-13866.
[46] Zhang B, Carroll J, Trojanowski JQ, et al.The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice[J]. J Neurosci, 2012, 32(11):3601-3611.
[47] Musiek ES, Xiong DD, Patel T, et al.Nmnat1 protects neuronal function without altering phospho-tau pathology in a mouse model of tauopathy[J]. Ann Clin Transl Neurol, 2016, 3(6):434-442.
[48] Jiang T, Tan L, Zhu XC, et al.Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice[J]. Neurobiol Aging, 2015, 36(12):3176-3186.
[49] Jiang T, Zhang YD, Chen Q, et al.TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice[J]. Neuropharmacology, 2016, 105:196-206.
[50] Elipenahli C, Stack C, Jainuddin S, et al.Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice[J]. J Alzheimers Dis, 2012, 28(1):173-182.
[51] Stack C, Jainuddin S, Elipenahli C, et al.Methylene blue upregulates Nrf2/ARE genes and prevents tau-related neurotoxicity[J]. Hum Mol Genet, 2014, 23(14):3716-3732.
[52] Ohia-Nwoko O, Montazari S, Lau YS, et al.Long-term treadmill exercise attenuates tau pathology in P301S tau transgenic mice[J]. Mol Neurodegener, 2014, 9:54.
[53] Koga S, Kojima A, Ishikawa C, et al.Effects of diet-induced obesity and voluntary exercise in a tauopathy mouse model: implications of persistent hyperleptinemia and enhanced astrocytic leptin receptor expression[J]. Neurobiol Dis, 2014, 71:180-192.
[54] Zhang Z, Song M, Liu X, et al.Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease[J]. Nat Med, 2014, 20(11):1254-1262.
[55] Barini E, Antico O, Zhao Y, et al.Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy[J]. Mol Neurodegener, 2016, 11:16.
[56] Allen B,Ingram E, Takao M, et al.Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein[J]. J Neurosci, 2002, 22(21): 9340-9351.
[57] Bellucci A, Westwood AJ, Ingram E, et al.Induction of inflammatory mediators andmicroglial activation in mice transgenic for mutant human P301Stau protein[J]. Am J Pathol, 2004, 165(5):1643-1652.
[58] Scattoni ML, Gasparini L, Alleva E, et al.Early behavioural markers of disease in P301S tau transgenic mice[J]. Behav Brain Res, 2010, 208(1):250-257.
[59] Rosenmann H, Grigoriadis N, Eldar-Levy H, et al.A noveltransgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics[J]. Exp Neurol, 2008, 212(1):71-84.