vestnik-bio-msuВестник Московского университета. Серия 16. БиологияVestnik Moskovskogo universiteta. Seriya 16. Biologiya0137-0952Lomonosov Moscow State University, School of Biologyvestnik-bio-msu-290Research ArticleГеронтологияGerontologyЭВОЛЮЦИЯ ПРЕДСТАВЛЕНИЙ О ПАТОГЕНЕЗЕ БОЛЕЗНИ АЛЬЦГЕЙМЕРАEVOLUTION OF UNDERSTANDING OF ALZHEIMER’S DISEASE PATHOGENESISСтефановаН. А.StefanovaN. A.

канд. биол. наук, научный сотрудник сектора молекулярных механизмов старения ИЦиГ СО РАН. Тел.: 8-383-363-49-80

stefanovan@bionet.nsc.ruКолосоваН. Г.KolosovaN. G.

докт. биол. наук, проф., зав. сектором молекулярных механизмов старения ИЦиГ СО РАН. Тел.: 8-383-363-49-80

kolosova@bionet.nsc.ruСектор молекулярных механизмов старения, Институт цитологии и генетики, СО РАН; Россия, 630090, г. Новосибирск, просп. Академика Лаврентьева, д. 10РоссияSector of Molecular Mechanisms of Aging, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrentyeva pr. 10, Novosibirsk, 630090, RussiaRussian FederationСектор молекулярных механизмов старения, Институт цитологии и генетики, СО РАН; Россия, 630090, г. Новосибирск, просп. Академика Лаврентьева, д. 10 кафедра цитологии и генетики, биологическое отделение, Новосибирский государственный университет; Россия, 630090, г. Новосибирск, ул. Пирогова, д. 2РоссияSector of Molecular Mechanisms of Aging, Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrentyeva pr. 10, Novosibirsk, 630090, Russia Chair of Cytology and Genetics, Department of Natural Sciences, Novosibirsk State University, Pirogova ul. 2, Novosibirsk, 630090, RussiaRussian Federation20161403201601613Copyright © Стефанова Н.А., Колосова Н.Г., 20162016Стефанова Н.А., Колосова Н.Г.Stefanova N.A., Kolosova N.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestnik-bio-msu.elpub.ru/jour/article/view/290

Болезнь Альцгеймера (БА) — нейродегенеративное заболевание, которое становится причиной деменции на фоне атрофических изменений мозга. Различают две формы БА: наследственную (НФБА; ~5% всех случаев заболевания, развивается до 65 лет, чаще — до 40–50 лет) и спорадическую (СФБА; ~95% всех случаев заболевания, развивается после 65 лет). Выявление генетических детерминант развития НФБА, доказательство нейротоксического действия пептида бета-амилоида (amyloid beta, Aβ) как центрального события в каскаде патологических процессов существенно расширили представления о молекулярно-генетических механизмах заболевания. Однако вопрос о том, является ли накопление Aβ инициирующим фактором развития наиболее распространенной СФБА остается открытым. Растет количество аргументов в пользу того, что гиперпродукция Аβ становится вторичным, сопутствующим событием патологических процессов БА: синаптической недостаточности, усиленного фосфорилирования тау-белка, нейровоспаления, гибели нейронов и снижения когнитивных функций. Как один из инициирующих факторов риска развития БА рассматривается митохондриальная дисфункция, следствием которой становится снижение синтеза АТФ, развитие окислительного стресса. Однако конкретные молекулярно-генетические механизмы развития БА остаются неясными. Это обусловлено отсутствием адекватных биологических моделей для изучения механизмов заболевания и объективной оценки эффективности патогенетически обоснованных способов профилактики и лечения БА.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is a cause of dementia that is linked to atrophic changes in the brain. There are two forms of AD: familial earlyonset form of AD (FAD, which accounts for ~5% of all cases) and sporadic late-onset AD (SAD, which accounts for ~95% of all cases). Identification of genetic determinants of FAD and proof of the neurotoxic effects of amyloid-beta peptide (Aβ) as a central event in the cascade of pathological processes significantly expanded understanding of the molecular and genetic mechanisms of the disease. However, the question of whether the accumulation of Aβ triggering factor for the most common SAD remain poorly understood. It is assumed that Aβ overproduction apparently becomes the secondary event of pathological processes of AD: synaptic failure, hyperphosphorylation of tau protein, neuroinflammation, neuronal loss and cognitive decline. As one of the risk factors for development of AD is mitochondrial dysfunction, a consequence of which becomes a decrease of ATP synthesis and oxidative stress. However, the specific molecular and genetic mechanisms of AD remain unclear. A major problem in AD research is the lack of an animal model that accurately replicates the human disease. This shortage makes it difficult to study the underlying mechanisms and to explore additional risk factors and therapeutic approaches to AD.

болезнь Альцгеймерабета-амилоидгиперфосфорилирование тау-белкасинапсынейровоспалениемитохондриальная дисфункцияобзорAlzheimer’s diseaseamyloid-betahyperphosphorylation of tau proteinsynapsesneuroinflammationmitochondrial dysfunctionreviewReferencesQuerfurth H.W., LaFerla F.M. Alzheimer’s disease // N. Engl. J. Med. 2010. Vol. 362. N 4. P. 329–344.Querfurth H.W., LaFerla F.M. Alzheimer’s disease // N. Engl. J. Med. 2010. Vol. 362. N 4. P. 329–344.Morley J.E., Armbrecht H.J., Farr S.A., Kumar V.B. The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease // Biochim. Biophys. Acta. 2012. Vol. 1822. N 5. P. 650–656.Morley J.E., Armbrecht H.J., Farr S.A., Kumar V.B. The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease // Biochim. Biophys. Acta. 2012. Vol. 1822. N 5. P. 650–656.Drachman D.A. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease // Alzheimers Dement. 2014. Vol. 10. N 3. P. 372–380.Drachman D.A. The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer’s disease // Alzheimers Dement. 2014. Vol. 10. N 3. P. 372–380.Ridge P.G., Ebbert M.T., Kauwe J.S. Genetics of Alzheimer’s disease // Biomed. Res. Int. 2013. Vol. 2013. Article ID 254954.Ridge P.G., Ebbert M.T., Kauwe J.S. Genetics of Alzheimer’s disease // Biomed. Res. Int. 2013. Vol. 2013. Article ID 254954.Guerreiro R., Bras J., Toombs J., Heslegrave J., Hardy J., Zetterberg H. Genetic variants and related biomarkers in sporadic Alzheimer’s disease // Curr. Genet. Med. Rep. 2015. Vol. 3. N 1. P. 19–25.Guerreiro R., Bras J., Toombs J., Heslegrave J., Hardy J., Zetterberg H. Genetic variants and related biomarkers in sporadic Alzheimer’s disease // Curr. Genet. Med. Rep. 2015. Vol. 3. N 1. P. 19–25.O’Brien R.J., Wong P.C. Amyloid precursor protein processing and Alzheimer’s disease // Annu. Rev. Neurosci. 2011. Vol. 34. P. 185–204.O’Brien R.J., Wong P.C. Amyloid precursor protein processing and Alzheimer’s disease // Annu. Rev. Neurosci. 2011. Vol. 34. P. 185–204.Puzzo D., Arancio O. Amyloid-β peptide: Dr. Jekyll or Mr. Hyde? // J. Alzheimers Dis. 2013. Vol. 33. N S1. P. S111–S120.Puzzo D., Arancio O. Amyloid-β peptide: Dr. Jekyll or Mr. Hyde? // J. Alzheimers Dis. 2013. Vol. 33. N S1. P. S111–S120.Jayadev S., Leverenz J.B., Steinbart E., Stahl J., Klunk W., Yu C.E., Bird T.D. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2 // Brain. 2010. Vol. 133. N 4. P. 1143–1154.Jayadev S., Leverenz J.B., Steinbart E., Stahl J., Klunk W., Yu C.E., Bird T.D. Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2 // Brain. 2010. Vol. 133. N 4. P. 1143–1154.DeMattos R.B., Cirrito J.R., Parsadanian M., May P.C., O’Dell M.A., Taylor J.W., Harmony J.A., Aronow B.J., Bales K.R., Paul S.M., Holtzman D.M. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo // Neuron. 2004. Vol. 41. N 2. P. 193–202.DeMattos R.B., Cirrito J.R., Parsadanian M., May P.C., O’Dell M.A., Taylor J.W., Harmony J.A., Aronow B.J., Bales K.R., Paul S.M., Holtzman D.M. ApoE and clusterin cooperatively suppress Abeta levels and deposition: evidence that ApoE regulates extracellular Abeta metabolism in vivo // Neuron. 2004. Vol. 41. N 2. P. 193–202.Thambisetty M., An Y., Kinsey A., Koka D., Saleem M., Güntert A., Kraut M., Ferrucci L., Davatzikos C., Lovestone S., Resnick S.M. Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment // Neuroimage. 2012. Vol. 59. N 1. P. 212–217.Thambisetty M., An Y., Kinsey A., Koka D., Saleem M., Güntert A., Kraut M., Ferrucci L., Davatzikos C., Lovestone S., Resnick S.M. Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment // Neuroimage. 2012. Vol. 59. N 1. P. 212–217.Jones L., Holmans P.A., Hamshere M.L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease // PLoS One. 2010. Vol. 5. N 11. e13950.Jones L., Holmans P.A., Hamshere M.L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease // PLoS One. 2010. Vol. 5. N 11. e13950.Armstrong R.A. The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis” // Int. J. Alzheimers Dis. 2011. Vol. 2011. Article ID 630865.Armstrong R.A. The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis” // Int. J. Alzheimers Dis. 2011. Vol. 2011. Article ID 630865.Cruchaga C., Chakraverty S., Mayo K. et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families // PLoS One. 2012. Vol. 7. N 2. e31039.Cruchaga C., Chakraverty S., Mayo K. et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families // PLoS One. 2012. Vol. 7. N 2. e31039.Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to thera peutics // Science. 2002. Vol. 297. N 5580. P. 353–356.Hardy J., Selkoe D.J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to thera peutics // Science. 2002. Vol. 297. N 5580. P. 353–356.Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W., Glabe C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis // Science. 2003. Vol. 300. N 5618. P. 486–489.Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W., Glabe C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis // Science. 2003. Vol. 300. N 5618. P. 486–489.Walsh D.M., Selkoe D.J. A beta oligomers — a decade of discovery // J. Neurochem. 2007. Vol. 101. N 5. P. 1172–1184.Walsh D.M., Selkoe D.J. A beta oligomers — a decade of discovery // J. Neurochem. 2007. Vol. 101. N 5. P. 1172–1184.Shankar G.M., Li S., Mehta T.H., Garcia-Munoz A., Shepardson N.E., Smith I., Brett F.M., Farrell M.A., Rowan M.J., Lemere C.A., Regan C.M., Walsh D.M., Sabatini B.L., Selkoe D.J. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory // Nat. Med. 2008. Vol. 14. N 8. P. 837–842.Shankar G.M., Li S., Mehta T.H., Garcia-Munoz A., Shepardson N.E., Smith I., Brett F.M., Farrell M.A., Rowan M.J., Lemere C.A., Regan C.M., Walsh D.M., Sabatini B.L., Selkoe D.J. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory // Nat. Med. 2008. Vol. 14. N 8. P. 837–842.El Khoury J., Toft M., Hickman S.E., Means T.K., Terada K., Geula C., Luster A.D. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimerlike disease // Nat. Med. 2007. Vol. 13. N 4. P. 432–438.El Khoury J., Toft M., Hickman S.E., Means T.K., Terada K., Geula C., Luster A.D. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimerlike disease // Nat. Med. 2007. Vol. 13. N 4. P. 432–438.Qiu W.Q., Walsh D.M., Ye Z., Vekrellis K., Zhang J., Podlisny M.B., Rosner M.R., Safavi A., Hersh L.B., Selkoe D.J. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation // J. Biol. Chem. 1998. Vol. 273. N 49. P. 32730–32738.Qiu W.Q., Walsh D.M., Ye Z., Vekrellis K., Zhang J., Podlisny M.B., Rosner M.R., Safavi A., Hersh L.B., Selkoe D.J. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation // J. Biol. Chem. 1998. Vol. 273. N 49. P. 32730–32738.Kanemitsu H., Tomiyama T., Mori H. Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form // Neurosci. Lett. 2003. Vol. 350. N 2. P. 113–116.Kanemitsu H., Tomiyama T., Mori H. Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form // Neurosci. Lett. 2003. Vol. 350. N 2. P. 113–116.Szabò I, Leanza L, Gulbins E, Zoratti M. Physiology of potassium channels in the inner membrane of mitochondria // Pflugers Arch. 2012. Vol. 463. N 2. P. 231–246.Szabò I, Leanza L, Gulbins E, Zoratti M. Physiology of potassium channels in the inner membrane of mitochondria // Pflugers Arch. 2012. Vol. 463. N 2. P. 231–246.Chaturvedi R.K., Flint Beal M. Mitochondrial diseases of the brain // Free Radic. Biol. Med. 2013. Vol. 63. P. 1–29.Chaturvedi R.K., Flint Beal M. Mitochondrial diseases of the brain // Free Radic. Biol. Med. 2013. Vol. 63. P. 1–29.Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease // Nat. Rev. Neurol. 2013. Vol. 9. N 1. P. 25–34.Krstic D., Knuesel I. Deciphering the mechanism underlying late-onset Alzheimer disease // Nat. Rev. Neurol. 2013. Vol. 9. N 1. P. 25–34.Roth M., Tomlinson B.E., Blessed G. Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects // Nature. 1966. Vol. 209. N 5018. P. 109–110.Roth M., Tomlinson B.E., Blessed G. Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects // Nature. 1966. Vol. 209. N 5018. P. 109–110.Spires-Jones T.L., Hyman B.T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease // Neuron. 2014. Vol. 82. N 4. P. 756–771.Spires-Jones T.L., Hyman B.T. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease // Neuron. 2014. Vol. 82. N 4. P. 756–771.Khlistunova I., Biernat J., Wang Y., Pickhardt M., von Bergen M., Gazova Z., Mandelkow E., Mandelkow E.M. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs // J. Biol. Chem. 2006. Vol. 281. N 2. P. 1205–1214.Khlistunova I., Biernat J., Wang Y., Pickhardt M., von Bergen M., Gazova Z., Mandelkow E., Mandelkow E.M. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs // J. Biol. Chem. 2006. Vol. 281. N 2. P. 1205–1214.Price J.L., McKeel Jr. D.W., Buckles V.D. et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease // Neurobiol. Aging. 2009. Vol. 30. N 7. P. 1026–1036.Price J.L., McKeel Jr. D.W., Buckles V.D. et al. Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease // Neurobiol. Aging. 2009. Vol. 30. N 7. P. 1026–1036.Spires-Jones T.L., Stoothoff W.H., de Calignon A., Jones P.B., Hyman B.T. Tau pathophysiology in neurodegeneration: a tangled issue // Trends Neurosci. 2009. Vol. 32. N 3. P. 150–159.Spires-Jones T.L., Stoothoff W.H., de Calignon A., Jones P.B., Hyman B.T. Tau pathophysiology in neurodegeneration: a tangled issue // Trends Neurosci. 2009. Vol. 32. N 3. P. 150–159.Terry R.D., Masliah E., Salmon D.P., Butters N., DeTeresa R., Hill R., Hansen L.A., Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment // Ann. Neurol. 1991. Vol. 30. N 4. P. 572–580.Terry R.D., Masliah E., Salmon D.P., Butters N., DeTeresa R., Hill R., Hansen L.A., Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment // Ann. Neurol. 1991. Vol. 30. N 4. P. 572–580.Wu H.Y., Hudry E., Hashimoto T., Kuchibhotla K., Rozkalne A., Fan Z., Spires-Jones T., Xie H., Arbel-Ornath M., Grosskreutz C.L., Bacskai B.J., Hyman B.T. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation // J. Neurosci. 2010. Vol. 30. N 7. P. 2636–2649.Wu H.Y., Hudry E., Hashimoto T., Kuchibhotla K., Rozkalne A., Fan Z., Spires-Jones T., Xie H., Arbel-Ornath M., Grosskreutz C.L., Bacskai B.J., Hyman B.T. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation // J. Neurosci. 2010. Vol. 30. N 7. P. 2636–2649.Balietti M., Giorgetti B., Casoli T., Solazzi M., Tamagnini F., Burattini C., Aicardi G., Fattoretti P. Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer’s disease // J. Alzheimers Dis. 2013. Vol. 34. N 4. P. 887–896.Balietti M., Giorgetti B., Casoli T., Solazzi M., Tamagnini F., Burattini C., Aicardi G., Fattoretti P. Early selective vulnerability of synapses and synaptic mitochondria in the hippocampal CA1 region of the Tg2576 mouse model of Alzheimer’s disease // J. Alzheimers Dis. 2013. Vol. 34. N 4. P. 887–896.Qu J., Nakamura T., Cao G., Holland E.A., McKercher S.R., Lipton S.A. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide // Proc. Natl. Acad. Sci. USA. 2011. Vol. 108. N 34. P. 14330–14335.Qu J., Nakamura T., Cao G., Holland E.A., McKercher S.R., Lipton S.A. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide // Proc. Natl. Acad. Sci. USA. 2011. Vol. 108. N 34. P. 14330–14335.D’Amelio M., Cavallucci V., Middei S. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease // Nat. Neurosci. 2011. Vol. 14. N 1. P. 69–76.D’Amelio M., Cavallucci V., Middei S. et al. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease // Nat. Neurosci. 2011. Vol. 14. N 1. P. 69–76.Kregel K.C., Zhang H.J. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations // Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007. Vol. 292. N 1. Р. 18–36.Kregel K.C., Zhang H.J. An integrated view of oxidative stress in aging: basic mechanisms, functional effects, and pathological considerations // Am. J. Physiol. Regul. Integr. Comp. Physiol. 2007. Vol. 292. N 1. Р. 18–36.Reczek C.R., Chandel N.S. ROS-dependent signal transduction // Curr. Opin. Cell Biol. 2015. Vol. 33. P. 8–13.Reczek C.R., Chandel N.S. ROS-dependent signal transduction // Curr. Opin. Cell Biol. 2015. Vol. 33. P. 8–13.Swerdlow R.H., Burns J.M., Khan S.M. The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives // Biochim. Biophys. Acta. 2014. Vol. 1842. N 8. P. 1219–1231.Swerdlow R.H., Burns J.M., Khan S.M. The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives // Biochim. Biophys. Acta. 2014. Vol. 1842. N 8. P. 1219–1231.Sierra A., Gottfried-Blackmore A.C., McEwen B.S., Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile // Glia. 2007. Vol. 55. N 4. Р. 412–424.Sierra A., Gottfried-Blackmore A.C., McEwen B.S., Bulloch K. Microglia derived from aging mice exhibit an altered inflammatory profile // Glia. 2007. Vol. 55. N 4. Р. 412–424.Kilbride S.M., Telford J.E., Tipton K.F., Davey G.P. Partial inhibition of complex I activity increases Ca2+-independent glutamate release rates from depolarized synaptosomes // J. Neurochem. 2008. Vol. 106. N 2. Р. 826–834.Kilbride S.M., Telford J.E., Tipton K.F., Davey G.P. Partial inhibition of complex I activity increases Ca2+-independent glutamate release rates from depolarized synaptosomes // J. Neurochem. 2008. Vol. 106. N 2. Р. 826–834.Moreira P.I., Honda K., Liu Q., Santos M.S., Oliveira C.R., Aliev G., Nunomura A., Zhu X., Smith M.A., Perry G. Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology // Curr. Alzheimer Res. 2005. Vol. 2. N 4. P. 403–408.Moreira P.I., Honda K., Liu Q., Santos M.S., Oliveira C.R., Aliev G., Nunomura A., Zhu X., Smith M.A., Perry G. Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology // Curr. Alzheimer Res. 2005. Vol. 2. N 4. P. 403–408.Devi L., Prabhu B.M., Galati D.F., Avadhani N.G., Anandatheerthavarada H.K. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction // J. Neurosci. 2006. Vol. 26. N 35. P. 9057–9068.Devi L., Prabhu B.M., Galati D.F., Avadhani N.G., Anandatheerthavarada H.K. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction // J. Neurosci. 2006. Vol. 26. N 35. P. 9057–9068.Atamna H., Boyle K. Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer’s disease // Proc. Natl. Acad. Sci. USA. 2006. Vol. 103. N 9. P. 3381–3386.Atamna H., Boyle K. Amyloid-beta peptide binds with heme to form a peroxidase: relationship to the cytopathologies of Alzheimer’s disease // Proc. Natl. Acad. Sci. USA. 2006. Vol. 103. N 9. P. 3381–3386.Cardoso S.M., Oliveira C.R. The role of calcineurin in amyloid-beta-peptides-mediated cell death // Brain Res. 2005. Vol. 1050. N 1-2. P. 1–7.Cardoso S.M., Oliveira C.R. The role of calcineurin in amyloid-beta-peptides-mediated cell death // Brain Res. 2005. Vol. 1050. N 1-2. P. 1–7.Manczak M., Calkins M.J., Reddy P.H. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage // Hum. Mol. Genet. 2011. Vol. 20. N 13. P. 2495–2509.Manczak M., Calkins M.J., Reddy P.H. Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer’s disease: implications for neuronal damage // Hum. Mol. Genet. 2011. Vol. 20. N 13. P. 2495–2509.Kolosova N.G., Stefanova N.A., Korbolina E.E., Fursova A.Zh., Kozhevnikova O.S. Senescence-accelerated OXYS rats: A genetic model of premature aging and age-related diseases // Adv. Gerontol. 2014. Vol. 4. N 4. P. 294–298.Kolosova N.G., Stefanova N.A., Korbolina E.E., Fursova A.Zh., Kozhevnikova O.S. Senescence-accelerated OXYS rats: A genetic model of premature aging and age-related diseases // Adv. Gerontol. 2014. Vol. 4. N 4. P. 294–298.Rudnitskaya E.A., Maksimova K.Y., Muraleva N.A., Logvinov S.V., Yanshole L.V., Kolosova N.G., Stefanova N.A. Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease // Biogerontology. 2015. Vol. 16. N 3. P. 303–316.Rudnitskaya E.A., Maksimova K.Y., Muraleva N.A., Logvinov S.V., Yanshole L.V., Kolosova N.G., Stefanova N.A. Beneficial effects of melatonin in a rat model of sporadic Alzheimer’s disease // Biogerontology. 2015. Vol. 16. N 3. P. 303–316.Rudnitskaya E.А., Muraleva N.A., Maksimova K.Y., Kiseleva E., Kolosova N.G., Stefanova N.A. Melatonin attenuates memory impairment, amyloid-β accumulation, and neurodegeneration in a rat model of sporadic Alzheimer’s disease // J. Alzheimers Dis. 2015. Vol. 47. P 103–116.Rudnitskaya E.А., Muraleva N.A., Maksimova K.Y., Kiseleva E., Kolosova N.G., Stefanova N.A. Melatonin attenuates memory impairment, amyloid-β accumulation, and neurodegeneration in a rat model of sporadic Alzheimer’s disease // J. Alzheimers Dis. 2015. Vol. 47. P 103–116.Stefanova N.A., Kozhevnikova O.S., Vitovtov A.O., Maksimova K.Y., Logvinov S.V., Rudnitskaya E.A., Korbolina E.E., Muraleva N.A., Kolosova N.G. Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease // Cell Cycle. 2014. Vol. 13. N 6. P. 898-909.Stefanova N.A., Kozhevnikova O.S., Vitovtov A.O., Maksimova K.Y., Logvinov S.V., Rudnitskaya E.A., Korbolina E.E., Muraleva N.A., Kolosova N.G. Senescence-accelerated OXYS rats: a model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease // Cell Cycle. 2014. Vol. 13. N 6. P. 898-909.Stefanova N.A., Maksimova K.Y., Kiseleva E., Rudnitskaya E.A., Muraleva N.A., Kolosova N.G. Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer’s disease-like pathology // J. Pineal. Res. 2015. Vol. 59. N 2. P. 163–177.Stefanova N.A., Maksimova K.Y., Kiseleva E., Rudnitskaya E.A., Muraleva N.A., Kolosova N.G. Melatonin attenuates impairments of structural hippocampal neuroplasticity in OXYS rats during active progression of Alzheimer’s disease-like pathology // J. Pineal. Res. 2015. Vol. 59. N 2. P. 163–177.Stefanova N.A., Muraleva N.A., Korbolina E.E., Kiseleva E., Maksimova K.Y., Kolosova N.G. Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats // Oncotarget. 2015. Vol. 6. N 3. P. 1396–1413.Stefanova N.A., Muraleva N.A., Korbolina E.E., Kiseleva E., Maksimova K.Y., Kolosova N.G. Amyloid accumulation is a late event in sporadic Alzheimer’s disease-like pathology in nontransgenic rats // Oncotarget. 2015. Vol. 6. N 3. P. 1396–1413.Stefanova N.A., Muraleva N.A., Skulachev V.P., Kolosova N.G. Alzheimer’s disease-like pathology in senescence- accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1 // J. Alzheimers Dis. 2014. Vol. 38. N 3. P. 681–694.Stefanova N.A., Muraleva N.A., Skulachev V.P., Kolosova N.G. Alzheimer’s disease-like pathology in senescence- accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1 // J. Alzheimers Dis. 2014. Vol. 38. N 3. P. 681–694.

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