阿尔茨海默病实验动物模型方法及评价

摘要/Abstract

摘要： 阿尔茨海默病（Alzheimer's Disease, AD）是一种神经退行性疾病，临床表现为认知功能障碍，病理学研究发现脑萎缩，细胞外老年斑（senile plaque, SP）沉积及细胞内出现神经纤维缠结（neurofibrillary tangle, NFT）。AD发病机制尚不清楚，因此动物模型的建立对探索其发病机制具有重要意义。本文就AD实验动物模型研究进展作一综述，详细描述并评价了目前常见的AD模型及其在药物研发中的应用。

关键词: 阿尔茨海默病, 动物模型, &, beta, 淀粉样蛋白, 认知, 记忆

Abstract: Alzheimer's disease (AD) is one of the neurodegenerative diseases with brain atrophy, extracellular senile plaques and intracellular neurofibrillary tangles. Animal disease models are an indispensible part in the evaluation of potential therapeutics. This review summarized current animal models of AD. A thorough and critical evaluation of current models of AD, and a discussion about their roles in drug discovery and development were included as well.

Key words: Alzheimer's disease, animal models, amyloid-&, beta, peptide, cognition, memory

中图分类号:

R965

王莹, 刘玉刚, 张丹参. 阿尔茨海默病实验动物模型方法及评价[J]. 神经药理学报, 2014, 4(2): 27-38.

WANG Ying, LIU Yu-gang, ZHANG Dan-shen. Animal Models of Alzheimer's Disease: a Review[J]. ACTA NEUROPHARMACOLOGICA, 2014, 4(2): 27-38.

参考文献

[1] Mattson M P. Pathways towards and away from Alzheimer’s disease[J]. Nature, 2004, 430(7000): 631-639.

[2] Mostany R，Anstey JE，Crump KL，et al. Altered synaptic dynamics during normal brain aging [J]. J Neurosci, 2013, 33(9): 4094-4104.

[3] Ni C, Tan G, Luo A, et al. Melatonin premedication Attenuates Isoflurane Anesthesia-Induced β-Amyloid Generation and Cholinergic Dysfunction in the Hippocampus of Aged Rats [J]. Int J Neurosci, 2013, 123(4): 213-220.

[4] Erickson C.A, Barnes C.A. The neurobiology of memory changes in normal aging [J]. Exp. Gerontol, 2003, 38(1): 61-69.

[5] Gupta VK, Scheunemann L, Eisenberg T, et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner [J]. Nat Neurosci, 2013, 16(10): 1453-1460.

[6] Takeda T. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 [J]. Neurochem Res, 2009, 34(4): 639-659.

[7] Takahashi R. Anti-aging studies on the senescence accelerated mouse (SAM) strains [J]. Yakugahu Zosshi, 2010, 130(1): 11-18.

[8] Garcfa-Matas S, Gutierrez-Cuesta J, Coto-Montes A. Dysfunction of astrocytes in senescence-accelerated mice SAMP8 reduces their neuroprotective capacity [J]. Aging Cell, 2008, 7(5): 630- 640.

[9] Tresguerres JA, Kireev R, Forman K, et al. Effect of chronic melatonin administration on several physiological parameters form old Wistar rats and SAMP8 mice [J]. Curr Aging Sci, 2012, 5(3): 242-253

[10] Sun CY, Qi SS, Zhou P, et al. Neurobiological and pharmacological validity of curcumin in ameliorating memory performance of senescence-accelerated mice [J]. Pharmacol Biochem Behav, 2013, 105:76-82

[11] Butterfield DA, Poon HF. The senescence accelerated prone mouse (SAMP8): a model of age related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease [J]. Exp Gerontol, 2005, 40(10): 774-783.

[12] Racchi M, Govoni S. The pharmacology of amyloid precursor protein processing [J] . Exp Gerontol, 2003, 38( 1-2) : 145-157.

[13] Meng QH, Lou FL, Hou WX, et al. Acetylpuerarin reduces inflammation and improves memory function in a rat model of Alzheimer's disease induced by Abeta1-42 [J]. Pharmazie, 2013, 68(11): 904-908.

[14] Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline [J]. Ann Intern Med, 2008, 148(5): 379-397.

[15] Yang S, Zhou G, Liu H, et al. Protective effects of p38 MAPK inhibitor SB202190 against hippocampal apoptosis and spatial learning and memory deficits in a rat model of vascular dementia [J]. Biomed Res Int, 2013, 2013:1-9.

[16] Van Dam D, De Deyn PP. Animal models in the drug discovery pipeline for Alzheimer’s disease [J]. Br J Pharmacol, 2011, 164(4):1285-1300.

[17] Matsuoka M, Ogata N, Minamino K, et al. Leukostasis and pigment epithelium-derived factor in rat models of diabetic retinopathy [J]. Mol Vis, 2007, 13: 1058-1065.

[18] Salkovic-Petrisic M, Osmanovic-Barilar J, Knezovic A. Long-term oral galactose treatment prevents cognitive deficits in male Wistar rats treated intracerebroventricularly with streptozotocin [J]. Neuropharmacology, 2014, 77: 68-80.

[19] Shanshan Z, Guichun Y, Lijun C, et al. Neuroprotective effects of edaravone on cognitive deficit, oxidative stress and tau hyperphosphorylation induced by intracerebroventricular streptozotocin in rats [J]. Neurotoxicology, 2013, 38: 136-145.

[20] Grunblatt E, Salkovic-Petrisic M, Osmanovic J, et al. Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein [J]. J Neurochem, 2007, 101(3): 757-770.

[21] 褚文政，钱采韻. 侧脑室注射链脲霉素引起大鼠脑Aβ1-40，Aβ1-42和tau202、tau396，tau404表达增加[J]. 第一军医大学学报，2005，25(2): 168-173.

[22] Lester-Coll N, Rivera EJ, Soscia SJ, et al. Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer's disease [J]. J Alzheimer's Dis, 2006, 9 (1): 13-33.

[23] Gong CX，Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease [J]. Curr Med Chem, 2008, 15(23): 2321-2328.

[24] Hernandez P, Lee G, Sjoberg M, et al. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ(25-35): Involvement of lipid rafts [J]. J Alzheimers Dis, 2009, 16(1): 149-56.

[25] Song XY, Hu JF, Chu SF, et al. Ginsenoside Rg1 attenuates okadaic acid induced spatial memory impairment by the GSK3β/tau signaling pathway and the Aβ formation prevention in rats [J]. Eur J Pharmacol, 2013, 710(1-3): 29-38.

[26] Kamat PK, Rai S, Nath C. Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer's disease pathology [J]. Neurotoxicology, 2013, 37: 163-172.

[27] Seung Yong Yoon, Jung Eun Choi, Ju Hee Yoon, et al. BACE inhibitor reduces APP-beta-C-terminal fragment accumulation in axonal swellings of okadaic acid induced neurodegeneration. Neurobiol Dis. 2006. 22 (2): 435-444.

[28] Ramirez C, Tercero I, Pineda A, et al. Simvastatin is the statin that most efficiently protects against kainate-induced excitotoxicity and memory impairment [J]. J Alzheimers Dis, 2011, 24(1): 161-174.

[29] Raghavendra M, Rituparna M, Shafalika K, et al. Role of aqueous extract of Azadirachta indica leaves in an experimental model of Alzheimer's disease in rats [J]. Int J Appl Basic Med Res, 2013, 3(1): 37-47.

[30] Hosseini N, Alaei H, Reisi P, et al. The effect of treadmill running on passive avoidance learning in animal model of Alzheimer disease [J]. Int J Prev Med, 2013, 4(2): 187-192.

[31] Park D, Joo SS, Kim TK, et al. Human neural stem cells overexpressing choline acetyltransferase restore cognitive function of kainic acid-induced learning and memory deficit animals [J]. Cell Transplant, 2012, 21(1): 365-371.

[32] Fisher A, Hanin I. Potential animal models for senile dementia of Alzheimer's type with emphasis on AF64-A induced cholinotoxicity [J]. Annu Rev Pharmacol Toxicol, 1986, 26: 161-181.

[33] 况伟宏，李进，王雪等. 乙基胆碱氮芥丙啶脑室内注射对大鼠空间学习记忆的影响研究 [J]. 中国行为医学科学，2004，13(1): 20-22.

[34] Dunnett SB, Everitt BJ, Robbins TW. The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions [J]. Trends Neurosci, 1991, 14(11): 494-501.

[35] Kumar A, Dogra S. Neuroprotective effect of carvedilol, an adrenergic antagonist against colchicines induced cognitive impairment and oxidative damage in rat [J]. Pharmacol Biochem Behav, 2009, 92(1): 25-31.

[36] Bensimon G, Chermat R. Microtubule disruption and cognitive defects: effect of colchicine on learning behavior in rats [J]. Pharmacol Biochem Behav 1991, 38(1): 141-145.

[37] Ming-Chin LU. Danggui Shaoyao San improve colchicine-induced learning acquisition impairment in rats[J]. Acta Pharmacol Sin, 2001, 22(12): 1149-1153.

[38] Saini N, Singh D, Sandhir R. Neuroprotective effects of Bacopa monnieri in experimental model of dementia [J]. Neurochem Res, 2012, 37(9): 1928-1937.

[39] Jellinger KA. The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations [J]. Int Rev Neurobiol, 2013, 110: 1-47.

[40] Jomova K, Valko M. Advances in metal induced oxidative stress and human disease [J]. Toxicology, 2011, 283(2-3): 65-87.

[41] Kawahara M. Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases[J]. J Alzheimers Dis, 2005, 8(2): 171-182.

[42] Li L, Chen RZ. Effect of intracerebroventricular injections of AlCl3 on the passive avoidance condition response in mice [J]. Chin J Pharmacol Toxicol, 1999, 13(4): 260-263.

[43] 商亚珍，缪红，程建军等. 黄芩茎叶总黄酮对铝中毒小鼠记忆障碍的作用 [J]. 中国药理学通报，2005，21(3):361-365

[44] 蒲韵竹. 斑马鱼阿尔茨海默病动物模型的建立 [M]. 重庆:西南大学，2013

[45] 方芳，晏勇. 老年性痴呆动物模型研究[J]. 国外医学：神经病学神经外科学分册，2004，31(5): 474-477.

[46] Parker WD Jr, Parks JK. Cytochrome c oxidase in Alzheimer’s disease brain: purification and characterization [J].Neurology, 1995, 45(3Pt1): 482-486.

[47] Luques L, ShohamS, Weinstock M. Chronic brain cytochrome oxidase inhibition selectively alters hippocampal cholinergic innervation and impairs memory: prevention by ladostigil [J]. Exp Neurol, 2007, 206(2): 209-219.

[48] Szabados T, Dul C, Majtenyi K, et al. A chronic Alzheimer's model evoked by mitochondrial poison sodium azide for pharmacological investigations [J]. Behav Brain Res, 2004, 154(1): 31-40.

[49] Bennett M C, Diamond D M, Stryker S L, et al. Cytochrome oxidase inhibition: a novel animal model of Alzheimer' s disease [J]. J Geriatr Psychiatry Neurol, 1992, 5(2): 93-101.

[50] Hozumi S, Ikezawa K, Shoji, et al. Simultaneous monitoring of excitatory postsynaptic potentials and extracellular L-glutamate in mouse hippocampal slices [J]. Biosens Bioelectron, 2011, 26(6): 2975-2980.

[51] 邱瑜，陈红专，金正均. 谷氨酸神经细胞毒作用的新途径——谷氨酸／胱氨酸转运体介导机制 [J]. 中国药理学通报，2000，16(3): 251-254.

[52] 马玉奎，渠广民. 蒺藜皂苷对谷氨酸致阿尔茨海默病模型小鼠的作用 [J]. 中国新药杂志，2009，18(6)：538-540.

[53] 刘晓丽，霍展样，刘世峰等. 谷氨酸钠对小鼠学习记忆能力及海马CA1区细胞数的影响 [J]. 新乡医学院学报，2002，19(3)：175-177.

[54] De La Torry JC. Critically attained threshold of cerebral hypoperfusion: can it cause Alzheimer's disease [J]. Ann N Y Acad Sci, 2000, 903: 424-436.

[55] Jeltsch H, Cassel JC, Neufang B, et al. The effects of intrahippocam palraphe and/or septal grafts in rats with fimbria-fornix lesions depend on the origin of the grafted tissue and the behavioural task used [J]. Neuroscience, 1994, 63(1): 19-39.

[56] Turgeon SM, Kegel G, Davis MM. Electrolytic lesions of the medial septum enhance latent inhibition in a conditioned taste aversion paradigm [J]. Brain Res, 2001, 890(2): 333-337.

[57] Pipatpiboon N, Pintana H, Pratchayasakul W, et al. DPP4-inhibitor improves neuronal insulin receptor function, brain mitochondrial function and cognitive function in rats with insulin resistance induced by high-fat diet consumption [J]. Eur J Neurosci, 2013, 37(5): 839-849.

[58] Clegg DJ, Gotoh K, Kemp C, et al. Consumption of a high-fat diet induces central insulin resistance independent of adiposity [J]. Physiol Behav, 2011, 103 (1): 10-16.

[59] Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, et al. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency [J]. Diabetes, 2006, 55(12): 3320-3325.

[60] Geschwind DH. Tau phosphorylation, tangles, and neurodegeneration: the chicken or the egg [J]. Neuron, 2003, 40(3):457-460.

[61] Craft S. Alzheimer disease: insulin resistance and AD-extending the translational path [J]. Nat Rev Neurol, 2012, 8(7): 360-362.

[62] Gibson GE, Blass JP. Thiamine-dependent processes and treatment strategies in neurodegeneration [J]. Antioxid Redox Sign, 2007, 9(10): 1605-1619.

[63] Gold M, Hauser RA, Chen MF. Plasma thiamine deficiency associated with Alzheimer's disease but not Parkinson's disease [J]. Metab Brain Dis, 1998, 13(1): 34-53.

[64] Karuppagounder SS, Xu H, Shi Q, et al. Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer' s mouse model [J]. Neurobiol Aging, 2009, 30(10): 1587-1600.

[65] 潘晓黎，赵艳玲，赵娜等. 硫胺素缺乏引起脑内β淀粉样蛋白沉积和tau蛋白磷酸化的增加 [J]. 中国临床神经科学，2009, 17 (3) , 235-239.

[66] McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer's disease in transgenic mice [J]. Trends Genet, 2006, 22(5): 281-289.

[67] Gordon MK, King DL, Diamond DM, et al. Correlation between cognitive deficits and Abeta deposits in transgenic APP+PSI mice [J]. Neuroboil Ageing, 2001, 22(3): 377-385.

[68] Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein [J]. Nature 1995, 373(6514): 523-527.

[69] Chen G, Chen KS, Knox J, et al. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease [J]. Nature, 2000, 408(6815): 975-979.

[70] Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice [J]. Science, 1996, 274(5284): 99-102.

[71] Kelly PH, Bondolfi L, Hunziker D, Progressive age-related impairment of cognitive behavior in APP23 transgenic mice [J]. Neurobiol Aging, 2003, 24(2): 365-378.

[72] Kalback W1, Watson MD, Kokjohn TA, et al. APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques [J]. Biochemistry, 2002, 41(3): 922-928.

[73] Goedert M, Klug A, Crowther RA. Tau protein, the paired helical filament and Alzheimer's disease [J]. J. Alzheimes Dis, 2006, 9(3 Suppl): 195-207.

[74] Gómez-Isla T1, Price JL, McKeel DW Jr, et al. Profound loss of layer II entorhinal cortex neurons distinguishes very mild Alzheimer's disease from nondemented aging [J]. J. Neurosci, 1996, 16(14), 4491-4500.

[75] Grundke-Iqbal, Iqbak K, Quinlan M, et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments [J]. J Biol Chem, 1986, 261(13): 6084-6089.

[76] Gotz J，Deters N，Doldissen A，et al． A decade of tau transgenic animal models and beyond [J]. Brain Pathol, 2007, 17(1): 91-103.

[77] Kemper AG, Weissmann C, Golovyashkina N, et al. The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner [J]. J Cell Biol, 2011, 192(4): 647-661.

[78] K. SantaCruz, J. Lewis, T. Spires, et al. Tau suppression in a neurodegenerative mouse model improves memory function [J]. Science, 2005, 309(5733): 476-481.

[79] Ramsden M, Kotilinek L, Forster C, et al. Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L) [J]. J Neurosci, 2005, 25(46): 10637-10647.

[80] Raber J, Huang Y, Ashford JW. ApoE genotype accounts for the vast majority of AD risk and AD pathology [J]. Neurobiol Aging, 2004, 25(5): 641-650.

[81] Gotz J, Ittner LM. Animal models of Alzheimer's disease and frontotemporal dementia [J]. Nat Rev Neurosci, 2008, 9(7): 532-544.

[82] Schmitz C, Rutten BP, Pielen A, et al. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease [J]. Am J Pathol, 2004, 164(4): 1495-1502.

[83] Duff K, Eckman C, Zehr C, et al.Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1[J]. Nature, 1996, 383(6602): 710-713.

[84] Begley JG, Duan W, Chan S, et al. Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice[J]. J Neurochem, 1999, 72(3): 1030-1039.

[85] Barrow PA, Empson RM, Gladwell SJ, et al. Functional phenotype in transgenic mice expressing mutant human presenilin-1[J]. Neurobiol Dis, 2000, 7(2): 119-126.

[86] Dai J, Buijs RM, Kamphorst W, et al. Impaired axonal transport of cortical neurons in Alzheimer' s disease is associated with neuropathological changes [J]. Brain Res, 2002, 948(1/2): 138-144.

[87] Stokin GB, Lillo C, Falzone TL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease [J]. Science, 2005, 307(5713): 1282-1288.

[88] Tucker KL, Meyer M, Barde YA. Neurotrophins are required for nerve growth during development [J]. Nat Neurosci, 2001, 4(1): 29-37.

[89] Polydoro M, Acker CM, Duff K, et al. Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology [J]. J Neurosci, 2009, 29(34): 10741-10749.

[90] Turner AJ, Isaac RE, Coates D The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function[J]. Bioessays, 2001, 23 (3) : 261-269.

[91] Mohajeri MH, Wolfer DP. Neprilysin deficiency-dependent impairment of cognitive functions in a mouse model of amyloidosis [J]. Neurochem Res 2009, 34(4): 717-726.

[92] Edbauer D, Willem M, Lammich S, et al. Insulin degrading enzyme rapidly removes the β-amyloid precursor protein intracellular domain (AICD) [J]. J Biol Chem, 2002, 277(16): 13389-13393.

[93] Farris W, Mansourian S, Chang Y, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo [J]. Proc Natl Acad Sci USA, 2003, 100(7): 4162-4167.

[94] Capsoni S, Ugolini G, Comparini A. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice [J]. Proc Natl Acad Sci USA 2000, 97(12): 6826-6831.

[95] Pesavento E, Capsoni S, Domenici L, et al. Acute cholinergic rescue of synaptic plasticity in the neurodegenerating cortex of antinerve-growth-factor mice [J]. Eur J Neurosci, 2002, 15(6): 1030-1036.

[96] Dickey CA, Loring JF, Montgomery J, et al. Selectively, reduced, expression of synaptic plasticity-related genes in amyloid precursor protein+preacnilin-1 tranagenic mice [J]. J Neurosci, 2003, 23(12): 5219-5230.

[97] Wengenack T M, Whelan S, Curran G L, et al. Quantitative histological analysis of amyloid deposition in Alzheimer' s double transgenic mouse brain [J]. Neuroscience, 2000, 101(4): 939-944.

[98] Lewis J, Dickson DW, Lin WL, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP [J]. Science, 2001, 293(5534): 1487-1491.

[99] Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction [J]. Neuron, 2003, 39(3): 409-421.

[100] Zheng H, Koo EH. The amyloid precursor protein: beyond amyloid [J]. Mol Neurodegener, 2006, 1: 5.

[101] Luo L, Tully T, White K. Human amyloid precursor protein ameliorates behavioral deficit of flies deleted for Appl gene [J]. Neuron, 1992, 9(4): 595-605.

[102] Fortini ME, Bonini NM. Modeling human neurodegenenrative diseases in Drosophila [J]. Trends in Genetics , 2000, 16 (4): 161-167.

[103] Lijima K, Liu HP, Chiang AS, et al. Dissecting the pathological effects of human Abeta40 and Abeta42 in drosophila: a potential model for Alzheimer's disease [J]. Proc Natl Acad Sci USA, 2004, 101(17): 6623-6628.

[104] Chatterjee S, Sang TK, Lawless GM, et al. Dissociation of tau toxicity and phosphorylation: role of GSK-3beta, MARK and Cdk5 in a Drosophila model [J]. Hum Mol Genet, 2009, 18(1): 164-177.

[105] Costa R, Speretta E, Crowther DC, et al. Testing the therapeutic potential of doxycycline in a Drosophila melanogaster model of Alzheimer disease [J]. J Biol Chem, 2011, 286(48): 41647−41655.

[106] Chakraborty R, Vepuri V, Mhatre SD, et al. Characterization of a drosophila Alzheimer’s disease model: pharmacological rescue of cognitive defects [J]. PLoS One, 2011, 6(6): e20799.