Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector17310.17816/psaic173ReviewsОбзорыUnknownModern pharmacological models of Alzheimer’s diseaseСовременные фармакологические модели болезни АльцгеймераKolobovV. V.КолобовВ. В.
Russian Federation
f.neurochemistry@gmail.comStorozhevaZ. I.СторожеваЗ. И.
Russian Federation
f.neurochemistry@gmail.comResearch Center of Neurology Russian Academy of Medical SciencesФГБУ «Научный центр неврологии» РАМНSerbsky National Research Centre for Social and Forensic PsychiatryФГБУ «Государственный научный центр социальной и судебной психиатрии им. В.П. Сербского» Минздрава России0909201483384401022017Copyright ©; 2014, Kolobov V.V., Storozheva Z.I.Copyright ©; 2014, Kolobov V.V., Storozheva Z.I.2014Kolobov V.V., Storozheva Z.I.Kolobov V.V., Storozheva Z.I.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/173

In vivo experimental models of Alzheimer’s disease are powerful tools for studying the mechanisms of pathogenesis and the search for new therapeutic agents. Pharmacological models, based on the injection of neurotoxins (beta-amyloid fragments, cholinotoxins, ibotenic acid) into the brain allow simulation the cognitive impairment typical for Alzheimer’s disease, and yield evaluation the impact of drugs on various indicators (biochemical, genetic, electrophysiological). The most validity was showed for the in vivo model of neurotoxic beta-amyloid fragments injection into basal forebrain nuclei.

Экспериментальные модели болезни Альцгеймера (БА) in vivo являются мощными инструментами для исследования механизмов патогенеза и поиска новых терапевтических средств. Фармакологические модели, основанные на введении в мозг нейротоксинов (бета-амилоидных фрагментов, холинотоксинов, иботеновой кислоты), позволяют воспроизводить характерные для БА когнитивные нарушения и оценивать эффективность влияния лекарственных препаратов на различные показатели (биохимические, генетические, электрофизиологические). Наибольшей наличной валидностью характеризуется in vivo модель введения нейротоксических бета-амилоидных фрагментов в базальные ядра переднего мозга.

Alzheimer’s diseaseexperimental modelsneurotoxic beta-amyloid fragmentsболезнь Альцгеймераэкспериментальные моделинейротоксические бета-амилоидные фрагментыАлександрова И.Ю., Кувичкин В.В., Кашпаров И.А. и др. Повышенный уровень бета-амилоида в мозге у бульбэктомированных мышей. Биохимия. 2004. 69 (2): 218–224.Бобкова Н.В., Нестерова И.В., Нестеров В.И. Состояние холинергических структур переднего мозга у бульбэктомированных мышей. Бюлл. экспер. биол. 2001; 131 (5): 507–511.Воронина Т.А., Островская Р.У. Методические указания по изучению ноотропной активности фармакологических веществ. Руководство по экспериментальному (доклиническому) изучению новых фармакологических веществ. Под ред. В.П. Фесенко.– М.: Ремедиум, 2000: 153–158.Горбатов В.Ю., Трекова Н.А. Фомина В.Г., Давыдова Т.В. Антиамнестическое действие антител к глутамату при экспериментальной болезни Альцгеймера. Бюл. экспер. биол. 2010; 150 (1): 28–30.Колобов В.В., Давыдова Т.В., Фомина В.Г. Защитное действие антител к глутамату на повышенную экспрессию генов программируемой гибели клеток головного мозга крыс, вызванной введением бета-амилоидного фрагмента (25–35). Известия Российской академии наук. Серия биологическая. 2014; 2: 133–141.Колобов В.В., Давыдова Т.В., Захарова И.А. и др. Репрессирующее влияние антител к глутамату на экспрессию гена Dffb в мозге крыс при экспериментальной болезни Альцгеймера. Молекуляр. биология. 2012; 46 (5): 757–765.43Колобов В.В., Фомина В.Г., Горбатов В.Ю., Давыдова Т.В. Сравнительный анализ эффектов антител к глутамату на нейрональную активность каспазы-3 и нарушения памяти у крыс, вызванные введением Аβ25-35 в ядра Мейнерта. Патол. физиология и экспер. терапия. 2013; 1: 27–32.Колобов В.В., Фомина В.Г., Давыдова Т.В. Антитела к глутамату снижают нейротоксические эффекты Аβ25-35 в транскриптоме клеток префронтальной коры головного мозга. Доклады Академии наук. 2012; 447 (3): 335–337.Островская Р.У., Бельник А.П., Сторожева З.И. Эффективность препарата “Ноопепт” при экспериментальной модели болезни Альцгеймера (когнитивный дефицит, вызванный введением β-амилоида25-35 в базальные ядра Мейнерта крыс). Бюл.экспер. биол. 2008; 146 (7): 84–88.Степаничев М.Ю., Гуляева Н.В. Инъекционные модели болезни Альцгеймера. Нейродегенеративные заболевания: фундаментальные и прикладные аспекты. Под ред. Угрюмова М.В. М.:Наука, 2010: 364–380.Сторожева З.И., Прошин А.Т., Жохов С.С. и др. Гексапептиды HLDF-6 и PEDF-6 восстанавливают память у крыс при хроническом введении бета-амилоидного пептида A-бета (25-35) в желудочки мозга. Бюл. экспер. биол. 2006; 141 (3): 292–296.Alzoubi K.H., Alhaider I.A., Tran T.T. et al. Impaired neural transmission and synaptic plasticity in superior cervical ganglia from β-amyloid rat model of Alzheimer’s disease. Curr Alzheimer Res. 2011; 8 (4): 377–384.Arif M., Kato T. Increased expression of PAD2 after repeated intracerebroventricular infusions of soluble Abeta(25-35) in the Alzheimer’s disease model rat brain: effect of memantine. Cell. Mol. Biol. Lett. 2009; 14 (4): 703–714.Ballmaier M., Casamenti F., Scali C. et al. Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis. Neuroscience. 2002; 114 (1): 91–98.Ballmaier M., Casamenti F., Zoli M. et al. Selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis impairs prepulse inhibition of acoustic startle. Neuroscience. 2001; 108 (2): 299–305.Bobkova N.V., Nesteroval I.V., Dana R. et al. Morphofunctional changes in neurons in the temporal cortex of the brain in relation to spatial memory in bulbectomized mice after treatment with mineral ascorbates. Neurosci. Behav. Physiol. 2004; 34 (7): 671–676.Borre Y., Bosman E., Lemstra S. et al. Memantine partly rescues behavioral and cognitive deficits in an animal model of neurodegeneration. Neuropharmacology. 2012; 62 (5–6): 2010–2017.Bures J., Buresova O., Huston J.P. Techniques and basic experiments for the study of brain behavior. Amsterdam: Elsevier, 1987.Casamenti F., Prosperi C., Scali C. et al. Morphological, biochemical and behavioural changes induced by neurotoxic and inflammatory insults to the nucleus basalis. Int. J. Dev. Neurosci. 1998; 16 (7–8): 705–714.Cetin F., Yazihan N., Dincer S., Akbulut G. The effect of intracerebroventricular injection of beta amyloid peptide (1-42) on caspase-3 activity, lipid peroxidation, nitric oxide and NOS expression in young adult and aged rat brain. Turk. Neurosurg. 2013; 23 (2): 144–150.Christensen R., Marcussen A.B., Wörtwein G. et al. Abeta(1–42) injection causes memory impairment, lowered cortical and serum BDNF levels, and decreased hippocampal 5 HT(2A) levels. Exp. Neurol. 2008; 210 (1): 164–171.Cummings J.L., Back C. The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer’s disease. Am. J. Geriatr. Psychiatry. 1998;6 (2, Suppl. 1): 64–78.Ding J., Xi Y.D., Zhang D.D. et al. Soybean isoflavone ameliorates β-amyloid 1-42-induced learning and memory deficit in rats by protecting synaptic structure and function. Synapse. 2013; 67 (12): 856–864.Fluhrer R., Haass Ch. Intramembrane proteolysis by γ-secretase and signal peptide peptidases. Intracellular traffic and neurodegenerative disorders. Eds. George-Hyslop P.H.St., Mobley W.C., Christen Y. Berlin: Springer, 2009: 11–26.Freir D.B., Holscher C., Herron C.E. Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo. J. Neurophysiol. 2001; 85 (2): 708–713.Ganguly R., Guha D. Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer’s disease & protection by Moringa oleifera. Indian. J. Med. Res. 2008; 128 (6): 744–751.Gengler S., Gault V.A., Harriott P., Hölscher C. Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background. Exp Brain Res. 2007; 179 (4): 621–630.Giovannelli L., Casamenti F., Scali C. et al. Differential effects ofamyloid peptides beta-(1-40) and beta-(25-35) injections into the rat nucleus basalis. Neurosci. 1995; 66 (4): 781–792.Giovannini M.G., Scali C., Prosperi C. et al. Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis. 2002; 11 (2): 257–274.Gritti I., Mainville L., Mancia M., Jones B.E. GABAergic and other noncholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat. J. Comp. Neurol. 1997; 383 (2): 163–177.Guo L.L., Guan Z.Z., Huang Y. et al. The neurotoxicity of β-amyloid peptide toward rat brain is associated with enhanced oxidative stress, inflammation and apoptosis, all of which can be attenuated by scutellarin. Exp Toxicol Pathol. 2013; 65 (5): 579–584.Haring J.H., Wang R.Y. The identification of some sources of afferent input to the rat nucleus basalis magnocellularis by retrograde transport of horseradish peroxidase. Brain Res. 1986; 366 (1–2): 152–158.Harkany T., Abrahám I., Timmerman W. et al. Beta amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur. J. Neurosci. 2000; 12 (8): 2735–2745.Harkany T., Mulder J., Sasvári M. et al. N-methyl-D-aspartate receptor antagonist MK-801 and radical scavengers protect cholinergic nucleus basalis neurons against beta-amyloid neurotoxicity. Neurobiol. Dis. 1999; 6 (2): 109–121.Harkany T., O′Mahony S., Kelly J.P. et al. Beta-amyloid (Phe(SO3H)24)25-35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation. Behav. Brain. Res. 1998; 90 (2): 133–145.Heuer E., Rosen R.F., Cintron A., Walker L.C. Nonhuman primate models of Alzheimer-like cerebral proteopathy. Curr. Pharm. Des. 2012; 18 (8): 1159–1169.Hiramatsu M., Inoue K., Kameyama T. Dynorphin A-(1-13) and (2-13) improve beta-amyloid peptide-induced amnesia in mice. Neuroreport. 2000; 11 (3): 431–435.Hruska Z., Dohanich G.P. The effects of chronic estradiol treatment on working memory deficits induced by combined infusion of betaamyloid (1-42) and ibotenic acid. Horm Behav. 2007; 52 (3): 297–306.Kubo T., Nishimura S., Kumagae Y., Kaneko I. In vivo conversion of racemized β-amyloid ([D Ser26]Aβ1–40) to truncated and toxic fragments ([D Ser26]Aβ25–35/40) and fragment presence in the brains of Alzheimer’s patients. J. Neurosci. Res. 2002; 70 (3): 474–483.Li Y., Qin H.Q., Chen Q.S., Wang J.J. Behavioral and neurochemical effects of the intrahippocampal co-injection of beta-amyloid protein 1-40 and ibotenic acid in rats. Int. J. Neurosci. 2004; 114 (12): 1521–1531.Matsumoto Y., Watanabe S., Suh Y.H., Yamamoto T. Effects of intrahippocampal CT105, a carboxyl terminal fragment of beta-amyloid precursor protein, alone/with inflammatory cytokines on working memory in rats. J. Neurochem. 2002; 82 (2): 234–239.Mesulam M.M., Mufson E.J., Wainer B.H., Levey A.I. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neurosci. 1983; 10 (4): 1185–1201.Miguel-Hidalgo J.J., Alvarez X.A., Cacabelos R., Quack G. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid (1-40). Brain Res. 2002; 958 (1): 210–221.Moriguchi S., Han F., Nakagawasai O. et al. Decreased calcium/calmodulin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. Neurochem. 2006; 97 (1): 22–29.Morimoto K., Yoshimi K., Tonohiro T. et al. Co-injection of betaamyloid with ibotenic acid induces synergistic loss46. Murphy C. Loss of olfactory function in dementing disease. Physiology & Behavior 1999; 66: 177–182.Nag S., Tang F., Yee B.K. Chronic intracerebroventricular exposure to beta-amyloid (1-40) impairs object recognition but does not affect spontaneous locomotor activity or sensorimotor gating in the rat. Exp. Brain. Res. 2001; 136 (1): 93–100.Nag S., Yee B.K., Tang F. Reduction in somatostatin and substance P levels and choline acetyltransferase activity in the cortex and hippocampus of the rat after chronic intracerebroventricular infusion of beta-amyloid (1–40). Brain Res. Bull. 1999; 50 (4): 251–262.Nakamura S., Murayama N., Noshita T. et al. Progressive brain dysfunction following intracerebroventricular infusion of beta(1-42)-amyloid peptide. Brain Res. 2001; 912 (2): 128–136.Nakamura S., Murayama N., Noshita T. et al. Cognitive dysfunction induced by sequential injection of amyloid-beta and ibotenate into the bilateral hippocampus; protection by memantine and MK-801. Eur. J. Pharmacol. 2006; 548 (1–3): 115–122.Park S., Kim D.S., Kang S., Moon N.R. β-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing β-cell mass in non-diabetic and diabetic rats. Metabolism 2013; http://dx.doi.org/10.1016/j.metabol.2013.08.007Peña F., Ordaz B., Balleza-Tapia H. et al. Beta-amyloid protein (25-35) disrupts hippocampal network activity: role of Fyn-kinase. Hippocampus. 2010; 20 (1): 78–96.Pike C.J., Walencewicz-Wasserman A.J., Kosmoski J. et al. Structureactivityanalyses of beta-amyloid peptides: contributions of the beta 25–35 region to aggregation and neurotoxicity. J. Neurochem. 1995; 64 (1): 253–265.Schindler H., Rush D.K., Fielding S. Nootropic drugs: animal models for studying effects on cognition. Drug Rev. Res. 1984; 4 (5):567–576.Souza L.C., Filho C.B., Goes A.T. et al. Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1-40 peptide. Neurotox. Res. 2013; 24 (2): 148–163.Stepanichev M.Y., Moiseeva Y.V., Lazareva N.A. et al. Single intracerebroventricular administration of amyloid-beta (25-35) peptide induces impairment in short-term rather than long-term memory in rats. Brain Res. Bull. 2003; 61 (2): 197–205.Stepanichev M.Y., Zdobnova I.M., Zarubenko I.I. et al. Differential effects of tumor necrosis factor-alpha co-administered with amyloid beta-peptide (25–35) on memory function and hippocampal damage in rat. Behav. Brain Res. 2006; 175 (1): 352–361.Stepanichev M.Y., Zdobnova I.M., Zarubenko I.I. et al. Amyloidbeta (25-35)-induced memory impairments correlate with cell loss in rat hippocampus. Physiol. Behav. – 2004; 80 (5): 647–655.Stock H.S., Hand G.A., Ford K., Wilson M.A. Changes in defensive behaviors following olfactory bulbectomy in male and female rats. Brain Res. 2001; 903 (1–2): 242–246.Storozheva Z.I., Proshin A.T., Sherstnev V.V. et al. Dicholine salt of succinic acid, a neuronal insulin sensitizer, ameliorates cognitive deficits in rodent models of normal aging, chronic cerebral hypoperfusion, and beta-amyloid peptide-(25-35)-induced amnesia. BMC Pharmacol. 2008; 8: 1. doi: 10.1186/1471-2210-8-1.Sun M.-K., Alkon D.L. Impairement of hippocampal heterosynaptic transformation and spatial memory by β-amyloid25-35. J. Neurophysiol. 2002; 87: 2441–2449.Trabace L., Kendrick K.M., Castrignanò S. et al. Soluble amyloid beta 1-42 reduces dopamine levels in rat prefrontal cortex: relationship to nitric oxide. Neuroscience. 2007; 147 (3): 652–663.Ueki A., Goto K., Sato N. et al. Prepulse inhibition of acoustic startle response in mild cognitive impairment and mild dementia of Alzheimer type. Psychiatry Clin. Neurosci. 2006; 60 (1): 55–62.von Linstow-Roloff E., Platt B., Riedel G. No spatial working memory deficit in beta-amyloid-exposed rats. A longitudinal study. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2002; 26 (5): 955–970.Yamamoto Y., Shioda N., Han F. et al. [Donepezil-induced neuroprotection of acetylcholinergic neurons in olfactory bulbectomized mice]. [Article in Japanese] Yakugaku Zasshi. 2010; 130 (5): 717–721.Yang SG, Wang SW, Zhao M. et al. A peptide binding to the β-site of APP improves spatial memory and attenuates Aβ burden in Alzheimer’s disease transgenic mice. PLoS One.2012; 7 (11): e48540. doi:10.1371/journal.pone.0048540.