Modeling Alzheimer’s disease in animals
https://doi.org/2618-6667-2018-77-97-108
Abstract
Alzheimer’s disease is a common neurodegenerative disease characterized by memory impairment and a progressive incurable cognitive decline. Modeling Alzheimer’s disease in animals allows to study the pathogenesis of the disease, to conduct preclinical studies, to search for possible ways to stop the development and progression of the disease. Since the etiology of Alzheimer’s disease remains unknown, there is no «natural» biological model that fully reflects the set of pathological disorders that occur in a person with this pathology, and among a variety of options of pathogenetic models there is no generally accepted one. This review provides an analysis of data on modern approaches to modeling Alzheimer’s disease in animals. The important aspects to be taken into account in modeling (metabolic disorders of β-amyloid and tau protein, the role of inflammatory reactions, etc.) have been analyzed. We review such widespread models as the use of transgenic animals of the frst and second generations expressing human genes with mutations found in the family form of the disease; models of natural aging and senescence-accelerated animals; intraventricular neurotoxin injection models. We also discuss more rare surgical models that phenotypically simulate some aspects of Alzheimer’s disease. An important role of inflammatory reactions in the pathogenesis of the disease is analyzed, which causes interest in models of neuroinflammation that manifests itself before the development of other pathological disorders characteristic for Alzheimer’s disease. We assess the advantages and limitations of each model, the features of their application, the main results obtained with their help, promising directions for further researches.
About the Authors
Anna Shmakova
FSBSI «Mental Health Research Centre», Moscow
Russian Federation
assistant researcher, laboratory of neuroimmunology
Russian Federation
assistant researcher, laboratory of neuroimmunology
Lyubov Androsova
FSBSI «Mental Health Research Centre», Moscow
Russian Federation
PhD, candidate of biological sciences, leading researcher, laboratory of neuroimmunology
Russian Federation
PhD, candidate of biological sciences, leading researcher, laboratory of neuroimmunology
References
1. Gulyaeva N.V;, Bobkova N.V., Kolosova N.G., Samokhin A.N., Stepanichev M.Y., Stefanova N.A. Molecular and cellular mechanisms of sporadic Alzheimer’s disease: Studies on Rodent Models in vivo. Biochemistry (Mosc). 2017;82(10):1088–1102. doi: 10.1371/journal. pone.0080706
2. Scheltens P., Blennow K., Breteler M.M., de Strooper B., Frisoni G.B., Salloway S., Van der Flier W.M. Alzheimer’s disease. Lancet. 2016;388(10043):505–517. doi: 10.1016/S0140-6736(15)01124-1
3. Winblad B., Amouyel P., Andrieu S., Ballard C., Brayne C., Brodaty H., Cedazo-Minguez A., Dubois B., Edvardsson D., Feldman H., Fratiglioni L., Frisoni G.B., Gauthier S., Georges J., Graff C., Iqbal K., Jessen F., Johansson G., Jönsson L., Kivipelto M., Knapp M., Mangialasche F., Melis R., Nordberg A., Rikkert M.O., Qiu C., Sakmar Т.P., Scheltens P., Schneider L.S., Sperling R., Tjernberg L.O., Walde- mar G., Wimo A., Zetterberg H. Defeating Alzheimer’s disease and other dementias: a priority for European science and society. Lancet Neurol. 2016;15(5):455–532. doi: 10.1016/S1474-4422(16)00062-4
4. Dementia. Fact sheet of WHO. December, 2017. Available at: http://www.who.int/mediacentre/factsheets/fs362/ru/. Accessed January 15, 2018.
5. Hyman B.T., Phelps C.H., Beach T.G., Bigio E.H., Cairns N.J., Carrillo M.C., Dickson D.W., Duyckaerts C., Frosch M.P., Masliah E., Mirra S.S., Nelson P.T., Schneider J.A., Thal D.R., Thies B., Trojanowski J.Q., Vinters H.V., Montine T.J. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic as- sessment of Alzheimer’s disease. Alzheimers Dement. 2012;8(1):1–13. doi: 10.1016/j.jalz.2011.10.007
6. LaFerla F.M., Green K.N. Animal models of Alzheimer disease. Cold Spring Harb Perspect. Med. 2012;2(11). doi: 10.1101/cshperspect. a006320
7. Kumar K., Kumar A., Keegan R.M., Deshmukh R. Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease. Biomed Pharmacother. 2017;98:297–307. doi: 10.1016/j. biopha.2017.12.053
8. Sasaguri H., Nilsson P., Hashimoto S., Nagata K., Saito T., De Strooper B., Hardy J., Vassar R., Winblad B., Saido T.C. APP mouse models for Alzheimer’s disease preclinical studies. EMBO J. 2017;36(17):2473–2487. doi: 10.15252/embj.201797397
9. 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. Hum. Genet. 1999;65(3):664–670. doi: 10.1086/302553
10. Priller C., Bauer T., Mitteregger G., Krebs B., Kretzschmar H.A., Herms J. Synapse formation and function is modulated by the amyloid precursor protein. J. Neurosci. 2006;26(27):7212–7221. doi: 10.1523/JNEUROSCI.1450-06.2006
11. Turner P.R., O’Connor K., Tate W.P., Abraham W.C. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog. Neurobiol. 2003;70(1):1–32.
12. Benedikz E., Kloskowska E., Winblad B. The rat as an animal model of Alzheimer’s disease. J. Cell Mol. Med. 2009;13(6):1034–1042. doi: 10.1111/j.1582-4934.2009.00781.x
13. Chávez-Gutiérrez L., Bammens L., Benilova I., Vandersteen A., Benurwar M., Borgers M., Lismont S., Zhou L., Van Cleynenbreugel S., Esselmann H., Wiltfang J., Serneels L., Karran E., Gijsen H., Schymkowitz J., Rousseau F., Broersen K., De Strooper B. The mechanism of γ-secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31(10):2261–2274. doi: 10.1007/s12035-012-8375-5
14. Rosenberg R.N., Lambracht-Washington D., Yu G., Xia W. Genomics of Alzheimer disease: a review. JAMA Neurol. 2016;73(7):867–874. doi: 10.1001/jamaneurol.2016.0301
15. Wisniewski T., Goñi F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85(6):1162–1176. doi: 10.1016/j.neuron.2014.12.064
16. Cavanaugh S.E., Pippin J.J., Barnard N.D. Animal models of Alz- heimer disease: historical pitfalls and a path forward. ALTEX. 2014;31(3):279–302. doi: 10.14573/altex.1310071
17. Heppner F.L., Ransohoff R.M., Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 2015;16(6):358–372. doi: 10.1038/nrn3880
18. Kliushnik T.P., Androsova L.V., Mikhailova N.M.., Sokolov A.V., Kostevich V.A., Zakharova E.T., Vasil’ev V.B. Potential markers of Alzheimer’s disease associated with inflammation. Psikhiatriya. 2014;1:28–34. (In Russ.).
19. Kliushnik T.P., Androsova L.V., Dupin A.M. Innate immunity and Alzheimer’s disease. Psikhiatriya. 2011;1:52–58. (In Russ.).
20. Androsova L.V., Mikhailova N.M., Zozulya S.A., Dupin A.M., Rassadina G.A., Lavrent’eva N.V., Kliushnik T.P. Inflammatory markers in Alzheimer’s disease and vascular dementia. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2013;113(2):49–53. (In Russ.).
21. Nazem A., Sankowski R., Bacher M., Al-Abed Y. Rodent models of neuroinflammation for Alzheimer’s disease. J. Neuroinflammation. 2015;12:74. doi: 10.1186/s12974-015-0291-y
22. Pizza V., Agresta A., D’Acunto C.W., Festa M., Capasso A. Neuroinflamm-aging and neurodegenerative diseases: an overview. CNS Neurol. Disord. Drug Targets. 2011;10(5):621–634.
23. Franceschi C., Capri M., Monti D., Giunta S., Olivieri F., Sevini F., Panourgia M.P., Invidia L., Celani L., Scurti M., Cevenini E., Castellani G.C., Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007;128(1):92–105. doi: 10.1016/ j.mad.2006.11.016
24. Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 2013;9(1):25–34. doi: 10.1038/nrneurol.2012.236
25. Voronina T.A., Ostrovskaya R.U. Metodicheskie ukazaniya po izucheniyu nootropnoi aktivnosti farmakologicheskikh veshchestv. Rukovodstvo po eksperimental’nomu (doklinicheskomu) izucheniyu novykh farmakologicheskikh veshchestv pod obshchei redaktsiei chlena-korrespondenta RAMN, professora R.U. Khabrie- va. Moskva: Meditsina; 2005:308–320. (In Russ.).
26. Stepanichev M.Y., Moiseeva Y.V., Lazareva N.A., Gulyaeva N.V. Studies of the effects of fragment (25–35) of beta-amyloid peptide on the behavior of rats in a radial maze. Neurosci. Behav. Physiol. 2005;35(5):511–518.
27. Tang F., Nag S., Shiu S.Y., Pang S.F. The effects of melatonin and Ginkgo biloba extract on memory loss and choline acetyltransferase activities in the brain of rats infused intracerebroventricularly with beta-amyloid 1-40. Life Sci. 2002;71(22):2625–2631.
28. Hashimoto M., Hossain S., Shimada T., Sugioka K., Yamasaki H., Fujii Y., Ishibashi Y., Oka J., Shido O. Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. J. Neurochem. 2002;81(5):1084–1091.
29. Haque A.M., Hashimoto M., Katakura M., Hara Y., Shido O. Green tea catechins prevent cognitive deficits caused by Abeta1-40 in rats. J. Nutr. Biochem. 2008;19(9):619–626. doi: 10.1016/j.jnut-bio.2007.08.008
30. Kolobov V.V., Storozheva Z.I. Modern pharmacological models of Alzheimer’s disease. Annaly klinicheskoi i eksperimental’noi nevrologii. 2014;8(3):38–44. (In Russ.).
31. de la Monte S.M., Wands J.R. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J. Alzheimers Dis. 2005;7(1):45–61.
32. Salkovic-Petrisic M., Knezovic A., Hoyer S., Riederer P. What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J. Neural. Transm. (Vienna). 2013;120(1):233–252. doi: 10.1007/s00702-012-0877-9
33. Salkovic-Petrisic M;, Osmanovic-Barilar J., Brückner M.K., Hoyer S., Arendt T., Riederer P. Cerebral amyloid angiopathy in streptozotocin rat model of sporadic Alzheimer’s disease: a long-term follow up study. J. Neural. Transm. (Vienna). 2011;118(5):765–772. doi: 10.1007/s00702-011-0651-4
34. Grieb P. Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol. Neurobiol. 2016;53(3):1741–1752. doi: 10.1134/S0006297917100029
35. Krügel U., Bigl V., Eschrich K., Bigl M. Deafferentation of the septo-hippocampal pathway in rats as a model of the metabolic events in Alzheimer’s disease. Int. J. Dev. Neurosci. 2001;19(3):263–277.
36. Hu J., Wang X., Liu D., Wang Q., Zhu L.Q. Olfactory deficits induce neurofilament hyperphosphorylation. Neurosci Lett. 2012;506(2):180–183. doi: 10.1016/j.neulet.2011.10.076
37. Avetisyan A.V., Samokhin A.N., Alexandrova I.Y., Zinovkin R.A., Simonyan R.A., Bobkova N.V. Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease. Biochemistry (Mosc). 2016;81(6):615–623. doi: 10.1134/S0006297916060080
38. Casas C., Sergeant N., Itier J.M., Blanchard V., Wirths O., van der Kolk N., Vingtdeux V., van de Steeg E., Ret G., Canton T., Drobecq H., Clark A., Bonici B., Delacourte A., Benavides J., Schmitz C., Tremp G., Bayer T. A., Benoit P., Pradier L. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am. J. Pathol. 2004;165(4):1289–1300.
39. Oakley H., Cole S.L., Logan S., Maus E., Shao P., Craft J., Guillozet-Bongaarts A., Ohno M., Disterhoft J., Van Eldik L., Berry R., Vassar R. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alz- heimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 2006;26(40):10129–10140. doi: 10.1523/JNEU- ROSCI.1202-06.2006
40. Ohno M., Cole S.L., Yasvoina M., Zhao J., Citron M., Berry R., Disterhoft J.F., Vassar R. BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol. Dis. 2007;26(1):134–145. doi: 10.1016/j.nbd.2006.12.008
41. Cebers G., Alexander R.C., Haeberlein S.B., Han D., Goldwater R., Ereshefsky L., Olsson T., Ye N., Rosen L., Russell M., Maltby J., Eketjäll S., Kugler A.R. AZD3293: Pharmacokinetic and pharmacody- namic effects in healthy subjects and patients with Alzheimer’s disease. J. Alzheimers Dis. 2017;55(3):1039–1053. doi: 10.3233/JAD- 160701
42. Götz J., Deters N., Doldissen A., Bokhari L., Ke Y., Wiesner A., Schonrock N., Ittner L.M. A decade of tau transgenic animal models and beyond. Brain Pathol. 2007;17(1):91–103. doi: 10.1007/s12035-015- 9132-3
43. Oddo S., Caccamo A., Shepherd J.D., Murphy M.P., Golde T.E., Kayed R., Metherate R., Mattson M.P., Akbari Y., LaFerla F.M. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39(3):409–421. doi: 10.1111/j.1582-4934.2008.00276.x
44. Oddo S. The ubiquitin-proteasome system in Alzheimer’s disease. J. Cell Mol. Med. 2008;12(2):363–373.
45. Keller J.N., Hanni K.B., Markesbery W.R. Impaired proteasome function in Alzheimer’s disease. J. Neurochem. 2000;75(1):436–439.
46. Janelsins M.C., Mastrangelo M.A., Oddo S., LaFerla F.M., Federoff H.J., Bowers W.J. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer’s disease mice. J. Neuroin- flammation. 2005;2:23. doi: 10.1186/1742-2094-2-23
47. Saido T.C., Iwatsubo T., Mann D.M., Shimada H., Ihara Y., Kawashima S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron. 1995;14(2):457–466.
48. Saito T., Matsuba Y., Mihira N., Takano J., Nilsson P., Itohara S., Iwata N., Saido T.C. Single App knock-in mouse models of Alzheimer’s disease. Nat. Neurosci. 2014;17(5):661–663. doi: 10.1038/nn.3697
49. Masuda A., Kobayashi Y., Kogo N., Saito T., Saido T.C., Itohara S. Cognitive deficits in single App knock-in mouse models. Neurobiol. Learn Mem. 2016;135:73–82. doi: 10.1016/j.nlm.2016.07.001
50. Zhang H., Wu L., Pchitskaya E., Zakharova O., Saito T., Saido T., Bezprozvanny I. Neuronal store-operated calcium entry and mushroom spine Loss in amyloid precursor protein knock-in mouse model of Alzheimer’s disease. J. Neurosci. 2015;35(39):13275–13286. doi: 10.1523/JNEUROSCI.1034-15.2015
51. Andorfer C., Kress Y., Espinoza M., de Silva R., Tucker K.L., Barde Y.A., Duff K., Davies P. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J. Neurochem. 2003;86(3):582–590.
52. Guo Q., Li H., Cole A.L., Hur J.Y., Li Y., Zheng H. Modeling Alzheimer’s disease in mouse without mutant protein overexpression: cooperative and independent effects of Aβ and tau. PLoS One. 2013;8(11):e80706. doi: 10.1111/j.1750-3639.2007.00051.x
53. Schor N.F. What the halted phase III γ-secretase inhibitor trial may (or may not) be telling us. Ann. Neurol. 2011;69(2):237–239. doi: 10.1002/ana.22365
54. Hu X., Hicks C.W,, He W., Wong P., Macklin W.B., Trapp B.D., Yan R. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci. 2006;9(12):1520–1525. doi: 10.1038/nn1797
55. Cheng X.R., Zhou W.X., Zhang Y.X. The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer’s disease animal model. Ageing Res. Rev. 2014;13:13–37. doi: 10.1038/emboj.2012.79
56. Manich G., del Valle J., Cabezón I., Camins A., Pallàs M., Pelegrí C., Vilaplana J. Presence of a neo-epitope and absence of amyloid beta and tau protein in degenerative hippocampal granules of aged mice. Age. 2014;36(1):151–165. doi: 10.1007/s11357-013-9560-9
57. Bosch M.N., Pugliese M., Gimeno-Bayón J., Rodríguez M.J., Mahy N. Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer’s disease. Curr. Alzheimer Res. 2012;9(3):298–314.
58. Sparks D.L., Schreurs B.G. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA. 2003;100(19):11065– 11069. doi: 10.1073/pnas.1832769100
59. Van Dam D., De Deyn P.P. Non human primate models for Alzheimer’s disease-related research and drug discovery. Expert Opin. Drug Discov. 2017;12(2):187–200. doi: 10.1080/17460441.2017.1271320
60. Krstic D., Madhusudan A., Doehner J., Vogel P., Notter T., Imhof C., Manalastas A., Hilfiker M., Pfister S., Schwerdel C., Riether C., Meyer U., Knuesel I. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflammation. 2012;9:151. doi: 10.1186/1742-2094-9-151
61. Kraska A., Santin M.D., Dorieux O., Joseph-Mathurin N., Bourrin E., Petit F., Jan C., Chaigneau M., Hantraye P., Lestage P., Dhenain M. In vivo cross-sectional characterization of cerebral alterations induced by intracerebroventricular administration of streptozotocin. PLoS One. 2012;7(9):e46196. doi: 10.1371/journal.pone.0046196
62. Chen Y., Liang Z., Blanchard J., Dai C.L., Sun S., Lee M.H., Grundke-Iqbal I., Iqbal K., Liu F., Gong C.X. A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol. Neurobiol. 2013;47(2):711–725. doi: 10.1016/j.arr.2013.10.002
63. Kamat P.K., Rai S., Swarnkar S., Shukla R., Nath C. Molecular and cellular mechanism of okadaic acid (OKA)-induced neurotoxicity: a novel tool for Alzheimer’s disease therapeutic application. Mol. Neurobiol. 2014;50(3):852–865. doi: 10.1007/s12035-014-8699-4
64. Kumar A., Seghal N., Naidu P.S., Padi S.S., Goyal R. Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer’s type. Pharmacol. Rep. 2007;59(3):274–283.
65. Ahlijanian M.K., Barrezueta N.X., Williams R.D., Jakowski A., Kowsz K.P., McCarthy S., Coskran T., Carlo A., Seymour P.A., Burkhardt J.E., Nelson R.B., McNeish J.D. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overex- pressing human p25, an activator of cdk5. Proc. Natl. Acad. Sci. USA. 2000;97(6):2910–2915. doi: 10.1073/pnas.040577797
66. Sundaram J.R., Chan E.S., Poore C.P., Pareek T.K., Cheong W.F., Shui G., Tang N., Low C.M., Wenk M.R, Kesavapany S. Cdk5/ p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurode- generation. J. Neurosci. 2012;32(3):1020–1034. doi: 10.1523/JNEU- ROSCI.5177-11.2012
67. Muyllaert D., Terwel D., Kremer A., Sennvik K., Borghgraef P., Devijver H., Dewachter I., Van Leuven F. Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. Am. J. Pathol. 2008;172(2):470–485. doi: 10.2353/ajpath.2008.070693
68. Fischer A., Sananbenesi F., Pang P.T., Lu B., Tsai L.H. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron. 2005;48(5):825–838. doi: 10.1016/j.neuron.2005.10.033
69. De Rosa R., Garcia A.A., Braschi C., Capsoni S., Maffei L., Berardi N., Cattaneo A. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc. Natl. Acad. Sci. USA. 2005;102(10):3811–3816. doi: 10.1073/pnas.0500195102
70. Houeland G., Romani A., Marchetti C., Amato G., Capsoni S., Cattaneo A., Marie H. Transgenic mice with chronic NGF deprivation and Alzheimer’s disease-like pathology display hippocampal region-specific impairments in short-and long-term plasticities. J. Neurosci. 2010;30(39):13089–13094. doi: 10.1523/JNEUROS- CI.0457-10.2010
71. Capsoni S., Brandi R., Arisi I., D’Onofrio M., Cattaneo A. A dual mechanism linking NGF/proNGF imbalance and early inflammation to Alzheimer’s disease neurodegeneration in the AD11 anti-NGF mouse model. CNS Neurol. Disord. Drug Targets. 2011;10(5):635–647.
Review
For citations:
Shmakova A., Androsova L. Modeling Alzheimer’s disease in animals. Psychiatry (Moscow) (Psikhiatriya). 2018;1(77):97-108. (In Russ.) https://doi.org/2618-6667-2018-77-97-108
Views:
2028
Email this article 
