阿尔茨海默病转基因小鼠模型特点和应用进展

doi:10.12300/j.issn.1674-5817.2021.182

实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (5): 432-439.DOI: 10.12300/j.issn.1674-5817.2021.182

阿尔茨海默病转基因小鼠模型特点和应用进展

魏枫(), 程维维, 尹雅芙()

上海交通大学医学院附属新华医院核医学科, 上海 200092

收稿日期:2021-12-13 修回日期:2022-05-21 出版日期:2022-10-25 发布日期:2022-11-04
通讯作者: 尹雅芙（1975—），女，博士生导师，主任医师，研究方向：核医学（脑/脊神经）。E-mail：Yinyf-2001@163.com。ORCID：0000000248186655
作者简介:魏枫（1996—），女，硕士研究生，研究方向：核医学（脑/脊神经）。E-mail： 514179650@qq.com
基金资助:
国家自然科学基金“基于多靶点分子影像技术的小胶质细胞自噬和极化调控在阿尔茨海默病细胞期治疗机制的研究”(81994290);上海市浦江人才计划“星形胶质细胞衰老和自噬在阿尔茨海默病发生发展中作用机制的分子靶向研究”(2019PJD032)

Characteristics and Application of Transgenic Mouse Models in Alzheimer's Disease

Feng WEI(), Weiwei CHENG, Yafu YIN()

Department of Nuclear Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China

Received:2021-12-13 Revised:2022-05-21 Published:2022-10-25 Online:2022-11-04
Contact: YIN Yafu (ORCID: 0000000248186655), E-mail: Yinyf-2001@163.com

摘要/Abstract

摘要：

阿尔茨海默病是一种常见的神经退行性疾病，临床主要表现为进行性记忆能力丧失和整体认知能力下降。两种典型的病理特征为在脑内检测到的老年斑和神经纤维缠结，分别由大量沉淀的淀粉样蛋白肽和过度磷酸化的Tau蛋白组成。除此之外还有神经炎性反应以及神经元广泛丢失等其他病理特征。在过去的几十年间虽然人们已经对阿尔茨海默病进行了大量的研究，但是其病因和发病机制仍不明确，至今也没有理想的治疗药物和根治方法。本综述介绍在临床前研究中使用的各种转基因动物模型的各自特点，及其目前在临床前研究中的应用情况，为未来的实验研究提供理论依据。

关键词: 阿尔茨海默病, 转基因小鼠, 动物模型, β淀粉样蛋白, Tau蛋白

Abstract:

Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss and overall cognitive decline. Two typical pathological features are senile plaques and neurofibrillary tangles detected in the brain, which consist of large amounts of precipitated amyloid peptide and hyperphosphorylated Tau protein, respectively. In addition, there are other pathological features such as neuroinflammatory response and extensive loss of neurons. In the past decades, a lot of research has been done on Alzheimer's disease, but its etiology and pathogenesis are still unclear, and there is no ideal treatment or radical cure. This review introduced the characteristics of various transgenic animal models and their current application in preclinical studies, in order to provide theoretical basis for future experimental studies.

Key words: Alzheimer's disease, Transgenic mouse, Animal models, β-amyloid protein, Tau protein

中图分类号:

Q95-33

魏枫, 程维维, 尹雅芙. 阿尔茨海默病转基因小鼠模型特点和应用进展[J]. 实验动物与比较医学, 2022, 42(5): 432-439.

Feng WEI, Weiwei CHENG, Yafu YIN. Characteristics and Application of Transgenic Mouse Models in Alzheimer's Disease[J]. Laboratory Animal and Comparative Medicine, 2022, 42(5): 432-439.

参考文献 45

1	JIA L F, DU Y F, CHU L, et al. Prevalence, risk factors, and management of dementia and mild cognitive impairment in adults aged 60 years or older in China: a cross-sectional study[J]. Lancet Public Health, 2020, 5(12): e661-e671. DOI:10.1016/S2468-2667(20)30185-7 .
2	WANG Y Q, JIA R X, LIANG J H, et al. Dementia in China (2015-2050) estimated using the 1% population sampling survey in 2015[J]. Geriatr Gerontol Int, 2019, 19(11):1096-1100. DOI:10.1111/ggi.13778 .
3	中国老龄协会.认知症老年人照护服务现状与发展报告[EB/OL].(2021-05-12)[2021-05-13]. .
4	BALLARD C, GAUTHIER S, CORBETT A, et al. Alzheimer's disease[J]. Lancet, 2011, 377(9770):1019-1031. DOI:10.1016/S0140-6736(10)61349-9 .
5	WELLER J, BUDSON A. Current understanding of Alzheimer's disease diagnosis and treatment[J]. F1000Res, 2018, 7: F1000 Faculty Rev-F1000 Faculty1161. DOI:10.12688/f1000research.14506.1 .
6	HANE F T, LEE B Y, LEONENKO Z. Recent progress in Alzheimer's disease research, part 1: pathology[J]. J Alzheimers Dis, 2017, 57(1):1-28. DOI:10.3233/JAD-160882 .
7	JONSSON T, ATWAL J K, STEINBERG S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline[J]. Nature, 2012, 488(7409):96-99. DOI:10.1038/nature11283 .
8	CHONG F P, NG K Y, KOH R Y, et al. Tau proteins and tauopathies in Alzheimer's disease[J].Cell Mol Neurobiol, 2018, 38(5):965-980. DOI:10.1007/s10571-017-0574-1 .
9	SAITO T, MATSUBA Y, MIHIRA N, et al. Single App knock-in mouse models of Alzheimer's disease[J]. Nat Neurosci, 2014, 17(5):661-663. DOI:10.1038/nn.3697 .
10	Masliah E, Sisk A, Mallory M, et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease [J]. J Neurosci, 1996, 16(18): 5795-5811.
11	CHEN G Q, CHEN K S, KNOX J, et al. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease[J]. Nature, 2000, 408(6815):975-979. DOI:10.1038/35050103 .
12	BEGLOPOULOS V, TULLOCH J, ROE A D, et al. Early detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice[J]. Nat Commun, 2016, 7:11761. DOI:10.1038/ncomms11761 .
13	SCOPA C, MARROCCO F, LATINA V, et al. Impaired adult neurogenesis is an early event in Alzheimer's disease neurodegeneration, mediated by intracellular Aβ oligomers[J]. Cell Death Differ, 2020, 27(3):934-948. DOI:10.1038/s41418-019-0409-3 .
14	KAWARABAYASHI T, YOUNKIN L H, SAIDO T C, et al. Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease[J]. J Neurosci, 2001, 21(2):372-381. DOI:10.1523/JNEUROSCI.21-02-00372.2001 .
15	DAM D V, VLOEBERGHS E, ABRAMOWSKI D, et al. APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder[J]. CNS Spectr, 2005, 10(3):207-222. DOI:10.1017/s1092852900010051 .
16	RIJAL UPADHAYA A, SCHEIBE F, KOSTERIN I, et al. The type of Aβ-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid β-peptide (APP48) transgenic mice[J]. Acta Neuropathol Commun, 2013, 1(1):77. DOI:10.1186/2051-5960-1-77 .
17	STURCHLER-PIERRAT C, ABRAMOWSKI D, DUKE M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology[J]. Proc Natl Acad Sci USA, 1997, 94(24):13287-13292. DOI:10.1073/pnas.94.24.13287 .
18	FLOOD D G, REAUME A G, DORFMAN K S, et al. FAD mutant PS-1 gene-targeted mice: increased Aβ42 and Aβ deposition without APP overproduction[J]. Neurobiol Aging, 2002, 23(3):335-348. DOI:10.1016/S0197-4580(01)00330-X .
19	ZHAO R H, HU W L, TSAI J, et al. Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer's disease[J]. Mol Neurodegeneration, 2017, 12(1):47. DOI:10.1186/s13024-017-0188-6 .
20	SHI Q Q, CHOWDHURY S, MA R, et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice[J]. Sci Transl Med, 2017, 9(392): eaaf6295. DOI:10.1126/scitranslmed.aaf6295 .
21	KIM T K, LEE J E, PARK S K, et al. Analysis of differential plaque depositions in the brains of Tg2576 and Tg-APPswe/PS1dE9 transgenic mouse models of Alzheimer disease[J]. Exp Mol Med, 2012, 44(8):492-502. DOI:10.3858/emm.2012.44.8.056 .
22	EIMER W A, VASSAR R. Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation[J]. Mol Neurodegener, 2013, 8:2. DOI:10.1186/1750-1326-8-2 .
23	MAZI A R, ARZUMAN A S, GUREL B, et al. Neonatal neurodegeneration in Alzheimer's disease transgenic mouse model[J]. J Alzheimers Dis Rep, 2018, 2(1):79-91. DOI:10.3233/ADR-170049 .
24	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. DOI:10.1126/science.274.5284.99 .
25	SPANGENBERG E E, LEE R J, NAJAFI A R, et al. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology[J]. Brain, 2016, 139(4):1265-1281. DOI:10.1093/brain/aww016 .
26	BAGLIETTO-VARGAS D, FORNER S, CAI L N, et al. Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology[J]. Nat Commun, 2021, 12:2421. DOI:10.1038/s41467-021-22624-z .
27	HUR J Y, FROST G R, WU X Z, et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease[J]. Nature, 2020, 586(7831):735-740. DOI:10.1038/s41586-020-2681-2 .
28	BALU D, KARSTENS A J, LOUKENAS E, et al. The role of APOE in transgenic mouse models of AD[J]. Neurosci Lett, 2019, 707:134285. DOI:10.1016/j.neulet.2019.134285 .
29	DUAN A R, JONASSON E M, ALBERICO E O, et al. Interactions between tau and different conformations of tubulin: implications for tau function and mechanism[J]. J Mol Biol, 2017, 429(9):1424-1438. DOI:10.1016/j.jmb.2017.03.018 .
30	GIACOBINI E, GOLD G. Alzheimer disease therapy—moving from amyloid-β to tau[J]. Nat Rev Neurol, 2013, 9(12):677-686. DOI:10.1038/nrneurol.2013.223 .
31	JOHNSON K A, SCHULTZ A, BETENSKY R A, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease[J]. Ann Neurol, 2016, 79(1):110-119. DOI:10.1002/ana.24546 .
32	LEWIS J, MCGOWAN E, ROCKWOOD J, et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein[J]. Nat Genet, 2000, 25(4):402-405. DOI:10.1038/78078 .
33	SAHARA N, LEWIS J, DETURE M, et al. Assembly of tau in transgenic animals expressing P301L tau: alteration of phosphorylation and solubility[J]. J Neurochem, 2002, 83(6):1498-1508. DOI:10.1046/j.1471-4159.2002.01241.x .
34	LEWIS J, DICKSON D W, LIN W L, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP[J]. Science, 2001, 293(5534):1487-1491. DOI:10.1126/science.1058189 .
35	D'ABRAMO C, ACKER C M, JIMENEZ H, et al. Passive immunization in JNPL3 transgenic mice using an array of phospho-tau specific antibodies[J]. PLoS One, 2015, 10(8): e0135774. DOI:10.1371/journal.pone.0135774 .
36	LAMBOURNE S L, HUMBY T, ISLES A R, et al. Impairments in impulse control in mice transgenic for the human FTDP-17 tau V337M mutation are exacerbated by age[J]. Hum Mol Genet, 2007, 16(14):1708-1719. DOI:10.1093/hmg/ddm119 .
37	TANEMURA K, MURAYAMA M, AKAGI T, et al. Neuro-degeneration with tau accumulation in a transgenic mouse expressing V337M human tau[J]. J Neurosci, 2002, 22(1):133-141. DOI:10.1523/jneurosci.22-01-00133.2002 .
38	SCHNÖDER L, GASPARONI G, NORDSTRÖM K, et al. Neuronal deficiency of p38α-MAPK ameliorates symptoms and pathology of APP or Tau-transgenic Alzheimer's mouse models[J]. FASEB J, 2020, 34(7):9628-9649. DOI:10.1096/fj. 201902731RR .
39	SAHARA N, VEGA I E, ISHIZAWA T, et al. Phosphorylated p38MAPK specific antibodies cross-react with sarkosyl-insoluble hyperphosphorylated tau proteins[J]. J Neurochem, 2004, 90(4):829-838. DOI:10.1111/j.1471-4159.2004.02558.x .
40	ODDO S, CACCAMO A, SHEPHERD J D, et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles[J]. Neuron, 2003, 39(3):409-421. DOI:10.1016/S0896-6273(03)00434-3 .
41	BILLINGS L M, ODDO S, GREEN K N, et al. Intraneuronal aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice[J]. Neuron, 2005, 45(5):675-688. DOI:10.1016/j.neuron.2005.01.040 .
42	HUBER C M, YEE C, MAY T, et al. Cognitive decline in preclinical Alzheimer's disease: amyloid-beta versus tauopathy[J]. J Alzheimers Dis, 2018, 61(1):265-281. DOI:10. 3233/JAD-170490 .
43	ESCARTIN C, GALEA E, LAKATOS A, et al. Reactive astrocyte nomenclature, definitions, and future directions[J]. Nat Neurosci, 2021, 24(3):312-325. DOI:10.1038/s41593-020-00783-4 .
44	BELFIORE R, RODIN A, FERREIRA E, et al. Temporal and regional progression of Alzheimer's disease-like pathology in 3xTg-AD mice[J]. Aging Cell, 2019, 18(1): e12873. DOI:10.1111/acel.12873
45	LE DOUCE J, MAUGARD M, VERAN J, et al. Impairment of glycolysis-derived 1-serine production in astrocytes contributes to cognitive deﬁcits in Alzheimer's disease[J]. Cell Metab, 2020, 31(3):503-517. DOI:10.1016/j.cmet.2020. 02.004 .

[1]	梁天薇, 邓亚胜, 黄慧, 荣娜, 刘鑫, 王玉洁, 林江. 围绝经期综合征动物模型的制备方法及评价指标分析[J]. 实验动物与比较医学, 2024, 44(1): 74-84.
[2]	中国研究型医院学会医学动物实验专家委员会. 自发性脑出血动物模型选择及临床前药物试验指南（2024年版）[J]. 实验动物与比较医学, 2024, 44(1): 3-30.
[3]	刘欣, 石少波, 张翠, 杨波, 曲川. 小鼠自体动静脉内瘘端侧吻合模型的建立与评价[J]. 实验动物与比较医学, 2023, 43(6): 595-603.
[4]	万颖寒, 顾也欣, 袁雨浓, 汤忞, 鲁立. FDA现代化法案2.0给疾病动物模型发展带来的启示和思考[J]. 实验动物与比较医学, 2023, 43(5): 472-481.
[5]	谢淑武, 沈如凌, 林金杏, 范春. 雄性不育药物研发相关实验动物模型建立和应用进展[J]. 实验动物与比较医学, 2023, 43(5): 504-511.
[6]	陈艳娟, 沈如凌. 模式动物疾病模型在结直肠癌医学研究中的应用进展[J]. 实验动物与比较医学, 2023, 43(5): 512-523.
[7]	张睿, 吕美豫, 张建军, 刘金莲, 陈彦, 黄志强, 刘尧, 周澜华. 痤疮动物模型建立及评价研究进展[J]. 实验动物与比较医学, 2023, 43(4): 398-405.
[8]	卢今, 王剑, 朱莲, 严国锋, 马政文, 李垚, 戴建军, 朱寅秋, 周晶. 山羊先兆子痫疾病模型的构建及母体生物学特性评价[J]. 实验动物与比较医学, 2023, 43(4): 371-380.
[9]	俞佳慧, 巩倩, 庄乐南. 肺动脉高压动物模型及其在药物研究中的应用进展[J]. 实验动物与比较医学, 2023, 43(4): 381-397.
[10]	邓亚胜, 林江, 甘池伶, 曾官凤, 黄嘉茵, 邓慧芳, 麻颖贤, 韩丝银. 皮肤光老化动物模型制备要素和受试物数据的文献分析[J]. 实验动物与比较医学, 2023, 43(4): 406-414.
[11]	王雪, 呼永河. 糖尿病小鼠模型的常见种类及其构建要素分析[J]. 实验动物与比较医学, 2023, 43(4): 415-421.
[12]	黄慧, 邓亚胜, 梁天薇, 郑艺清, 范燕萍, 荣娜, 林江. 卵巢储备功能减退动物模型的造模方法评价与分析[J]. 实验动物与比较医学, 2023, 43(4): 422-428.
[13]	相磊, 景金珠, 梁震, 阎国强, 郭文峰, 张萌, 张威, 刘亚军. 基于VOSviewer的肌少症动物模型研究可视化分析[J]. 实验动物与比较医学, 2023, 43(4): 429-439.
[14]	谭志刚, 刘锦信, 郑楚雅, 廖文峰, 冯露平, 彭红丽, 严秀, 卓振建. 神经母细胞瘤动物模型研究进展与应用[J]. 实验动物与比较医学, 2023, 43(3): 288-296.
[15]	赖灿, 李乐乐, 胡塔拉, 孟彦. 肾脏间质纤维化动物模型的研究进展[J]. 实验动物与比较医学, 2023, 43(2): 163-172.

阿尔茨海默病转基因小鼠模型特点和应用进展

Characteristics and Application of Transgenic Mouse Models in Alzheimer's Disease

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献 45

相关文章 15

编辑推荐

Metrics

本文评价