psychiatryПСИХИАТРИЯPsychiatry (Moscow) (Psikhiatriya)1683-83192618-6667FSBSI “The Mental Health Research Centre”; LLC «Publisher «MIA»2618-6667-2018-77-97-108psychiatry-320Research ArticleНАУЧНЫЕ ОБЗОРЫSCIENTIFIC REVIEWSМоделирование болезни Альцгеймера на животныхModeling Alzheimer’s disease in animalsШмаковаАнна АндреевнаShmakovaAnna

лаборант-исследователь, лаборатория нейроиммунологии

assistant researcher, laboratory of neuroimmunology

anya.shmakova@list.ruАндросоваЛюбовь ВасильевнаAndrosovaLyubov

кандидат биологических наук, ведущий научный сотрудник, лабораториянейроиммунологии

PhD, candidate of biological sciences, leading researcher, laboratory of neuroimmunology

androsL@mail.ruФГБНУ «Научный центр психического здоровья», МоскваРоссияFSBSI «Mental Health Research Centre», MoscowRussian Federation20183110201817797108Copyright © Шмакова А.А., Андросова Л.В., 20182018Шмакова А.А., Андросова Л.В.Shmakova A., Androsova L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.journalpsychiatry.com/jour/article/view/320

Болезнь Альцгеймера (БА) — распространенное нейродегенеративное заболевание, которое характеризуется нарушениями памяти и прогрессирующим неизлечимым снижением когнитивных функций. Моделирование БА на животных позволяет изучать патогенез заболевания, проводить доклинические испытания лекарственных препаратов, искать возможные способы приостановить развитие и прогрессирование заболевания. Так как этиология БА остается неизвестной, то не существует «естественной» биологической модели, позволяющей полностью отразить совокупность патологических нарушений, возникающих у человека с данной патологией, а среди разнообразия вариантов патогенетических моделей нет общепринятой. В настоящем обзоре приведен анализ данных литературы о современных подходах к моделированию БА на животных. Разобраны важные аспекты заболевания, которые необходимо учитывать при моделировании (нарушения метаболизма β-амилоида и тау-белка, роль воспалительных реакций и др.). Рассмотрены такие распространенные модели, как использование трансгенных животных первого и второго поколений, экспрессирующих человеческие гены с мутациями, обнаруженными при семейной форме заболевания; модели естественного и ускоренного старения; инъекционные модели, заключающиеся во внутрижелудочковом введении нейротоксинов. Обсуждены и более редкие хирургические модели, фенотипически имитирующие картину БА. Анализируется важная роль воспалительных реакций в патогенезе заболевания, обусловливающая интерес к моделям нейровоспаления, манифестирующего до развития других патологических нарушений, характерных для БА. Оценены преимущества и недостатки каждой модели, особенности их применения, основные результаты, полученные с их помощью, перспективные направления для дальнейших исследований.

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.

болезнь Альцгеймера (БА)экспериментальные моделидоклинические моделимодели на животныхAlzheimer’s diseaseexperimental modelspreclinical studiesanimal modelsReferencesGulyaeva 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.0080706Gulyaeva 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.0080706Scheltens 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)01124-1Scheltens 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)01124-1Winblad 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., Mangi J alasche 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 cWinblad 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)00062-4Деменция. Информационный бюллетень ВОЗ. Декабрь 2017 г. URL: http://www.who.int/mediacentre/factsheets/fs362/ru/. Ссылка активна на 15.01.2018.Dementia. Fact sheet of WHO. December, 2017. Available at: http://www.who.int/mediacentre/factsheets/fs362/ru/. Accessed January 15, 2018.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., r 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 Agj ing-Alzheimer’s Association guidelines for the neuropathologic asi sessment of Alzheimer’s disease. Alzheimers Dement. 2012;8(1):1–13. s doi: 10.1016/j.jalz.2011.10.007Hyman 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.2011.10.007LaFerla F.M., Green K.N. Animal models of Alzheimer disease. Cold Spring Harb Perspect. Med. 2012;2(11). doi: 10.1101/cshperspect. a006320LaFerla F.M., Green K.N. Animal models of Alzheimer disease. Cold Spring Harb Perspect. Med. 2012;2(11). doi: 10.1101/cshperspect. a006320Kumar 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.2017.12.053Kumar 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.2017.12.053Sasaguri 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.201797397Sasaguri 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.201797397Campion 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: 10.1086/302553Campion 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: 10.1086/302553Priller 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.1450-06.2006Priller 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.1450-06.2006Turner 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.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.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.xBenedikz 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.xChávez-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/s12035-012-8375-5Chávez-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/s12035-012-8375-5Rosenberg 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.2016.0301Rosenberg 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.2016.0301Wisniewski T., Goñi F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85(6):1162–1176. doi: 10.1016/j.neuron.2014.12.064Wisniewski T., Goñi F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85(6):1162–1176. doi: 10.1016/j.neuron.2014.12.064Cavanaugh S.E., Pippin J.J., Barnard N.D. Animal models of Alzheimer disease: historical pitfalls and a path forward. ALTEX. 2014;31(3):279–302. doi: 10.14573/altex.1310071Cavanaugh 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.1310071Heppner 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/nrn3880Heppner 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/nrn3880Клюшник Т.П., Андросова Л.В., Михайлова Н.М., Соколов А.В., Костевич В.А., Захарова Е.Т., Васильев В.Б. Потенциальные маркеры болезни Альцгеймера, ассоциированные с воспалением. Психиатрия. 2014;1:28–34.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.).Клюшник Т.П., Андросова Л.В., Дупин А.М. Врожденный иммунитет и болезнь Альцгеймера. Психиатрия. 2011;1:52–58.Kliushnik T.P., Androsova L.V., Dupin A.M. Innate immunity and Alzheimer’s disease. Psikhiatriya. 2011;1:52–58. (In Russ.).Андросова Л.В., Михайлова Н.М., Зозуля С.А., Дупин А.М., Рассадина Г.А., Лаврентьева Н.В., Клюшник Т.П. Маркеры воспаления при болезни Альцгеймера и сосудистой деменции. Журнал неврологии и психиатрии им. С.С. Корсакова. 2013;113(2):49–53.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.).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-yNazem 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-yPizza 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.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.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 sys- temic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 2007;128(1):92–105. doi: 10.1016/ j.mad.2006.11.016Franceschi 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.2006.11.016Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 2013;9(1):25–34. doi: 10.1038/nrneurol.2012.236Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease. Nat. Rev. Neurol. 2013;9(1):25–34. doi: 10.1038/nrneurol.2012.236Воронина Т.А., Островская Р.У. Методические указания по изучению ноотропной активности фармакологических веществ. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ под общей редакцией члена-корреспондента РАМН, профессора Р.У. Хабриева. М.: Медицина; 2005:308–320.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.).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.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.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.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.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.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.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.jnutbio.2007.08.008Haque 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.2007.08.008Колобов В.В., Сторожева З.И. Современные фармакологические модели болезни Альцгеймера. Анналы клинической и экспериментальной неврологии. 2014;8(3):38–44.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.).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.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.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/s00702-012-0877-9Salkovic-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/s00702-012-0877-9Salkovic-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/s00702-011-0651-4Salkovic-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/s00702-011-0651-4Grieb 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/S0006297917100029Grieb 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/S0006297917100029Krügel 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.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.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.2011.10.076Hu 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.2011.10.076Avetisyan 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/S0006297916060080Avetisyan 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/S0006297916060080Casas C., Sergeant N., Itier J.M., Blanchard V., Wirths O., van der Kolk N., Vingtdeux V., van de Steeg E., Ret G., Canton T., Dro- becq 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.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.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 Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 2006;26(40):10129–10140. doi: 10.1523/JNEU- ROSCI.1202-06.2006Oakley 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.1202-06.2006Ohno 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.2006.12.008Ohno 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.2006.12.008Cebers 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 pharmacodynamic effects in healthy subjects and patients with Alzheimer’s disease. J. Alzheimers Dis. 2017;55(3):1039–1053. doi: 10.3233/JAD- 160701Cebers 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- 160701Götz 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- 9132-3Götz 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- 9132-3Oddo 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.xOddo 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.xOddo S. The ubiquitin-proteasome system in Alzheimer’s disease. J. Cell Mol. Med. 2008;12(2):363–373.Oddo S. The ubiquitin-proteasome system in Alzheimer’s disease. J. Cell Mol. Med. 2008;12(2):363–373.Keller J.N., Hanni K.B., Markesbery W.R. Impaired proteasome function in Alzheimer’s disease. J. Neurochem. 2000;75(1):436–439.Keller J.N., Hanni K.B., Markesbery W.R. Impaired proteasome function in Alzheimer’s disease. J. Neurochem. 2000;75(1):436–439.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: 10.1186/1742-2094-2-23Janelsins 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: 10.1186/1742-2094-2-23Saido 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.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.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.3697Saito 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.3697Masuda 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.2016.07.001Masuda 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.2016.07.001Zhang H., Wu L., Pchitskaya E., Zakharova O., Saito T., Saido T., Bezprozvanny I. Neuronal store-operated calcium entry and mush- room 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.1034-15.2015Zhang 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.1034-15.2015Andorfer 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.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.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.xGuo 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.xSchor 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.22365Schor 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.22365Hu 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/ nn1797Hu 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/nn1797Cheng 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.2012.79Cheng 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.2012.79Manich 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/s11357-013-9560-9Manich 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/s11357-013-9560-9Bosch 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.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.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.1832769100Sparks 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.1832769100Van 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: 10.1080/17460441.2017.1271320Van 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: 10.1080/17460441.2017.1271320Krstic 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: 10.1186/1742-2094-9-151Krstic 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: 10.1186/1742-2094-9-151Kraska 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.0046196Kraska 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.0046196Chen Y., Liang Z., Blanchard J., Dai C.L., Sun S., Lee M.H., Grund- ke-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.2013.10.002Chen 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.2013.10.002Kamat 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/s12035-014-8699-4Kamat 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/s12035-014-8699-4Kumar A., Seghal N., Naidu P.S., Padi S.S., Goyal R. Colchicines-in- duced neurotoxicity as an animal model of sporadic dementia of Alzheimer’s type. Pharmacol. Rep. 2007;59(3):274–283.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.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.040577797Ahlijanian 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.040577797Sundaram 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 neurodegeneration. J. Neurosci. 2012;32(3):1020–1034. doi: 10.1523/JNEU- ROSCI.5177-11.2012Sundaram 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.5177-11.2012Muyllaert 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.2008.070693Muyllaert 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.2008.070693Fischer 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.2005.10.033Fischer 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.2005.10.033De 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.0500195102De 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.0500195102Houeland 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 shortand long-term plasticities. J. Neurosci. 2010;30(39):13089–13094. doi: 10.1523/JNEUROS- CI.0457-10.2010Houeland 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.0457-10.2010Capsoni S., Brandi R., Arisi I., D’Onofrio M., Cattaneo A. A dual mech- anism 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.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.

The authors declare that there are no conflicts of interest present.