medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2019-12-34-40medsovet-3130Research ArticleНЕВРОЛОГИЯNEUROLOGYРоль митохондриальной дисфункции при болезни АльцгеймераThe role of mitochondrial dysfunction in Alzheimer’s diseaseКоберскаяН. Н.KoberskayaN. N.

Коберская Надежда Николаевна - кандидат медицинских наук, ассистент кафедры нервных болезней и нейрохирургии лечебного факультета.

119991, Москва, ул. Трубецкая, д. 8, стр. 2; 119991, Москва, ул. Б. Пироговская, д. 6, стр. 1; тел.: +7 (985) 22202-63

Koberskaya Nadezhda Nikolaevna - Cand. of Sci. (Med.), Associate Professor of Chair for Nervous Diseases and Neurosurgery, Faculty of General Medicine.

119991, Moscow, Trubetskaya Str., 8, Bldg. 2; 119991, Moscow, B. Pirogovskaya St.,6, Bldg. 1; Tel.: +7 (985) 222-02-63

koberskaya_n_n@mail.ruФедеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет имени И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский университет)РоссияFederal State Autonomous Educational Institution of Higher Education Sechenov First Moscow State Medical University of the Ministry of Heath of the Russian Federation (Sechenov University)Russian Federation2019290820190123440Copyright © Коберская Н.Н., 20192019Коберская Н.Н.Koberskaya N.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/3130

В данном обзоре приводятся и обсуждаются доказательства, демонстрирующие важность митохондрий и связанных с ними процессов в патогенезе болезни Альцгеймера. Обсуждается митохондриальная дисфункция как потенциально возможная терапевтическая мишень при лечении болезни Альцгеймера и других нейродегенеративных заболеваний, а также различные лекарственные стратегии, направленные на нарушение функций митохондрий и развитие окислительного стресса.

This review presents and discusses evidence demonstrating the importance of mitochondria and related processes in the pathogenesis of Alzheimer's disease. Mitochondrial dysfunction is currently emerging as a potential therapeutic target in the treatment of Alzheimer's disease and other neurodegenerative diseases. This paper also reviews various drug strategies aimed at mitochondrial dysfunction and the development of oxidative stress.

болезнь Альцгеймерамитохондриямитохондриальная дисфункцияоксидативный стресскоэнзим 010идебенонAlzheimer’s diseasemitochondriamitochondrial dysfunctionoxidative stresscoenzyme 010idebenonReferencesKumar A., Singh A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions. Front. Pharmacol. 2015;6:206.Kumar A., Singh A. A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions. Front. Pharmacol. 2015;6:206.Парфенов В.А. Ранняя диагностика и лечение болезни Альцгеймера. Медицинский совет. 2015;5:28-33.Parfenov V.A. Early diagnosis and treatment of Alzheimer's disease. Meditsinsky Sovet, 2015;5:28-33. (In Russ).Alzheimer's A. Alzheimer's disease facts and figures. Alzheimer's Dement. 2015;11:332-384.Alzheimer's A. Alzheimer's disease facts and figures. Alzheimer's Dement. 2015;11:332-384.Swerdlow R.H., Burns J.M., Khan S.M. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim. Biophys. Acta. 2014:1842,1219-1231.Swerdlow R.H., Burns J.M., Khan S.M. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim. Biophys. Acta. 2014:1842,1219-1231.Eckert G.P. and Muller W.E. Mitochondrial dysfunction: cause and consequence of Alzheimer's. Mitochondrion Aging Dis. 2014:127,183-210.Eckert G.P. and Muller W.E. Mitochondrial dysfunction: cause and consequence of Alzheimer's. Mitochondrion Aging Dis. 2014:127,183-210.Du H. and Yan S.S. Mitochondrial medicine for neurodegenerative diseases. Int. J. Biochem. Cell Biol. 2010;42:560-572.Du H. and Yan S.S. Mitochondrial medicine for neurodegenerative diseases. Int. J. Biochem. Cell Biol. 2010;42:560-572.Moreira P.I., Carvalho C., Zhu X. et al. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim. Biophys. Acta. 2010:1802,2-10.Moreira P.I., Carvalho C., Zhu X. et al. Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. Biochim. Biophys. Acta. 2010:1802,2-10.Muller T., Buttner T., Gholipour A.-F. Kuhn W. Coenzyme Q 10 supplementation provидебенонs mild symptomatic benefit in Patients with Parkinson's disease. Neurosci. Lett. 2003;341:201-204.Muller T., Buttner T., Gholipour A.-F. Kuhn W. Coenzyme Q 10 supplementation provидебенонs mild symptomatic benefit in Patients with Parkinson's disease. Neurosci. Lett. 2003;341:201-204.Bergamasco B., Scarzella L. La C.P. Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol. 1994;9:161-168.Bergamasco B., Scarzella L. La C.P. Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol. 1994;9:161-168.Ahmed E. Moneim. Oxidant/Antioxidant Imbalance and the Risk of Alzheimer's Disease. Current Alzheimer Research. 2015;12:335-349.Ahmed E. Moneim. Oxidant/Antioxidant Imbalance and the Risk of Alzheimer's Disease. Current Alzheimer Research. 2015;12:335-349.Hauptmann S., Scherping I., Drose S., Brandt U., Schulz K.L., Jendrach M., et al. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging. 2009;30(10):1574-1586.Hauptmann S., Scherping I., Drose S., Brandt U., Schulz K.L., Jendrach M., et al. Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging. 2009;30(10):1574-1586.Meier T., Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009; 256(Suppl 1):25-30.Meier T., Buyse G. Idebenone: an emerging therapy for Friedreich ataxia. J Neurol. 2009; 256(Suppl 1):25-30.Eckert A., Schmitt K., Gtz J. Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid- toxicity. Alzheimers. Res. Ther. 2011 Vol. 3,2:15.Eckert A., Schmitt K., Gtz J. Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid- toxicity. Alzheimers. Res. Ther. 2011 Vol. 3,2:15.Swerdlow R.H., Khan S.M. A «mitochondrial cascade Hypothesis» for sporadic Alzheimer'sdisease. Med. Hypotheses. 2004;63:8-20.Swerdlow R.H., Khan S.M. A «mitochondrial cascade Hypothesis» for sporadic Alzheimer'sdisease. Med. Hypotheses. 2004;63:8-20.Witte M.E., Geurts JJ., De Vries H.E. et al. Mitochondrial dysfunction: a potential link between neuro inflammation and neurodegeneration? Mitochondrion. 2010;10:411-418.Witte M.E., Geurts JJ., De Vries H.E. et al. Mitochondrial dysfunction: a potential link between neuro inflammation and neurodegeneration? Mitochondrion. 2010;10:411-418.Leuner K., Mller W.E., Reichert A.S. From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer's disease. Mol. Neurobiol. 2012; 46,1:186-193.Leuner K., Mller W.E., Reichert A.S. From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer's disease. Mol. Neurobiol. 2012; 46,1:186-193.Caspersen C., Wang N., Yao J., Sosunov A., Chen X. , Lustbader J.W., Xu H.W., Stern D., McKhann G., Yan S. Du. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease, FASEB J. 2005;19,14:2040-2041.Caspersen C., Wang N., Yao J., Sosunov A., Chen X. , Lustbader J.W., Xu H.W., Stern D., McKhann G., Yan S. Du. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease, FASEB J. 2005;19,14:2040-2041.Nakamura T., Watanabe A., Fujino T., Hosono T., Michikawa M. Apolipoprotein E (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol. Neurodegener. 2009;4,1:35-46.Nakamura T., Watanabe A., Fujino T., Hosono T., Michikawa M. Apolipoprotein E (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol. Neurodegener. 2009;4,1:35-46.Calkins MJ., Manczak M., Reddy P.H. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease. Pharmaceuticals (Basel). 2012;5(10):1103-1119.Calkins MJ., Manczak M., Reddy P.H. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease. Pharmaceuticals (Basel). 2012;5(10):1103-1119.Zhu X., Perry G., Smith M.A., Wang X. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2013;33(1):253-262.Zhu X., Perry G., Smith M.A., Wang X. Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Alzheimers Dis. 2013;33(1):253-262.Lakatos A., Derbeneva O., Younes D. et al. Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort. Neurobiol. Aging. 2010;31:1355-1363.Lakatos A., Derbeneva O., Younes D. et al. Association between mitochondrial DNA variations and Alzheimer's disease in the ADNI cohort. Neurobiol. Aging. 2010;31:1355-1363.Hung C.H.-L., Ho Y.-S., Chang R.C.-C. Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease. Ageing Res. Rev. Elsevier B.V., 2010;9,4:447-456.Hung C.H.-L., Ho Y.-S., Chang R.C.-C. Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease. Ageing Res. Rev. Elsevier B.V., 2010;9,4:447-456.Maruszak A., Zekanowski C., Mitochondrial dysfunction and Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2011;35:320-330.Maruszak A., Zekanowski C., Mitochondrial dysfunction and Alzheimer's disease. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2011;35:320-330.Wang X., Su B., Siedlak S.L. et al. Amyloid-b over production causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl. Acad. Sci. U.S.A. 2008;105:19318-19323.Wang X., Su B., Siedlak S.L. et al. Amyloid-b over production causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc. Natl. Acad. Sci. U.S.A. 2008;105:19318-19323.Galpern W.R., Cudkowicz M.E. Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion. 2007;7:146-153.Galpern W.R., Cudkowicz M.E. Coenzyme Q treatment of neurodegenerative diseases of aging. Mitochondrion. 2007;7:146-153.Bambrick L.L., Fiskum G. Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res. 2008;1188:9-16.Bambrick L.L., Fiskum G. Mitochondrial dysfunction in mouse trisomy 16 brain. Brain Res. 2008;1188:9-16.Festenstein G.N., Heaton F.W., Lowe J.S., Morton RA. A constituent of the unsaponifiable portion of animal tissue lipids (lambda max. 272 m mu). Biochem J. 1955;59(4):558-566.Festenstein G.N., Heaton F.W., Lowe J.S., Morton RA. A constituent of the unsaponifiable portion of animal tissue lipids (lambda max. 272 m mu). Biochem J. 1955;59(4):558-566.Crane F.L., Hatefi Y., Lester R.L., WidmerC. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta. 1957;25(1):220-221.Crane F.L., Hatefi Y., Lester R.L., WidmerC. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta. 1957;25(1):220-221.Crane F.L. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001;20(6):591-598.Crane F.L. Biochemical functions of coenzyme Q10. J Am Coll Nutr. 2001;20(6):591-598.Dumont M., Kipiani K., Yu F., Wille E., Katz M., Calingasan N.Y., et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2011;27(1):211-223.Dumont M., Kipiani K., Yu F., Wille E., Katz M., Calingasan N.Y., et al. Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2011;27(1):211-223.Turunen M., Olsson J., Dallner G. Metabolism and function of coenzyme Q. Biochim. Biophys. Acta. 2004;1660:171-199.Turunen M., Olsson J., Dallner G. Metabolism and function of coenzyme Q. Biochim. Biophys. Acta. 2004;1660:171-199.Ishrat T., Khan M.B., Hoda M.N. еt al.Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav. Brain Res. 2006;171:9-16.Ishrat T., Khan M.B., Hoda M.N. еt al.Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav. Brain Res. 2006;171:9-16.McGarry A., McDermott M., Kieburtz K., de Blieck E.A., Beal F., Marder K., Ross C., Shoulson I., Gilbert P., Mallonee W.M., et al. A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology. 2017;88(2):152-59.McGarry A., McDermott M., Kieburtz K., de Blieck E.A., Beal F., Marder K., Ross C., Shoulson I., Gilbert P., Mallonee W.M., et al. A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology. 2017;88(2):152-59.Kaufmann P., Thompson J.L., Levy G. et al. Phase II trial of CoQ 10 for ALS finds in sufficient evидебенoнnce to Justify phase III. Ann.Neurol. 2009;66:235-244.Kaufmann P., Thompson J.L., Levy G. et al. Phase II trial of CoQ 10 for ALS finds in sufficient evидебенoнnce to Justify phase III. Ann.Neurol. 2009;66:235-244.Senin U., Parnetti L., Barbagallo-Sangiorgi G. еt al.Idebenone in senile dementia of Alzheimer type: a multicenter study. Arch.Gerontol.Geriatr. 1992;15:249-260.Senin U., Parnetti L., Barbagallo-Sangiorgi G. еt al.Idebenone in senile dementia of Alzheimer type: a multicenter study. Arch.Gerontol.Geriatr. 1992;15:249-260.Parkinson M.H., Schulz J.B., Giunti P. Coenzyme Q10 and idebenone use in Friedreich's ataxia. J Neurochem. 2013;126(Suppl 1):125-141.Parkinson M.H., Schulz J.B., Giunti P. Coenzyme Q10 and idebenone use in Friedreich's ataxia. J Neurochem. 2013;126(Suppl 1):125-141.Di Prospero N.A., Baker A., Jeffries N., Fischbeck K.H. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6:878-886.Di Prospero N.A., Baker A., Jeffries N., Fischbeck K.H. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 2007;6:878-886.Meier T., Perlman S.L., Rummey C., Coppard NJ., Lynch D.R. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol. 2012; 259:284-291.Meier T., Perlman S.L., Rummey C., Coppard NJ., Lynch D.R. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich's ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol. 2012; 259:284-291.Weyer G., Babej-Dolle R., Hadler D., Hofmann S., Herrmann W. A Controlled study of 2 doses of idebenone in the treatment of Alzheimer'sdisease. Neuropsychobiology 1997;36:73-82.Weyer G., Babej-Dolle R., Hadler D., Hofmann S., Herrmann W. A Controlled study of 2 doses of idebenone in the treatment of Alzheimer'sdisease. Neuropsychobiology 1997;36:73-82.Gutzmann H., Kuhl K., Hadler D., Rapp M.A.Safety and efficacy of idebenone versus tacrine in patients with Alzheimer'sdisease: Results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry. 2002;35:12-18.Gutzmann H., Kuhl K., Hadler D., Rapp M.A.Safety and efficacy of idebenone versus tacrine in patients with Alzheimer'sdisease: Results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry. 2002;35:12-18.Thal LJ., Grundman M., Berg J., Ernstrom K. et al. idebenone treatment fails to slow cognitive decline in Alzheimer's disease. Neurology 2003;61(11):1498-1502.Thal LJ., Grundman M., Berg J., Ernstrom K. et al. idebenone treatment fails to slow cognitive decline in Alzheimer's disease. Neurology 2003;61(11):1498-1502.Yamada K., Tanaka T., Han D., Senzaki K., Kameyama T., Nabeshima T. Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. Eur J Neurosci. 1999;11:83-90.Yamada K., Tanaka T., Han D., Senzaki K., Kameyama T., Nabeshima T. Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. Eur J Neurosci. 1999;11:83-90.Bruno V., Battaglia G., Copani A., Sortino M.A., Canonico P.L., Nicoletti F. Protective action of idebenone against excitotoxic degeneration in cultured cortical neurons. Neurosci Lett. 1994;178:193-196.Bruno V., Battaglia G., Copani A., Sortino M.A., Canonico P.L., Nicoletti F. Protective action of idebenone against excitotoxic degeneration in cultured cortical neurons. Neurosci Lett. 1994;178:193-196.Ranen N.G., Peyser C.E., Coyle J.T., Bylsma F.W., Sherr M., Day L., Folstein M.F., Brandt J., Ross C.A., Folstein S.E. A controlled trial of idebenone in Huntington's disease. Mov Disord. 1996;11:549-554.Ranen N.G., Peyser C.E., Coyle J.T., Bylsma F.W., Sherr M., Day L., Folstein M.F., Brandt J., Ross C.A., Folstein S.E. A controlled trial of idebenone in Huntington's disease. Mov Disord. 1996;11:549-554.McDonald C.M., Meier T., Voit T., Schara U., Straathof C.S., D'Angelo M.G., Bernert G., Cuisset J.M., Finkel R.S., Goemans N., et al. Idebenone reduces respiratory complications in patients with Duchennemuscular dystrophy. Neuromuscul. Disord. 2016;26:473-480.McDonald C.M., Meier T., Voit T., Schara U., Straathof C.S., D'Angelo M.G., Bernert G., Cuisset J.M., Finkel R.S., Goemans N., et al. Idebenone reduces respiratory complications in patients with Duchennemuscular dystrophy. Neuromuscul. Disord. 2016;26:473-480.Montenegro L., Turnaturi R., Parenti C., Pasquinucci L.. Idebenone: Novel Strategies to Improve Its Systemicand Local Efficacy. Nanomaterials. 2018;8:87.Montenegro L., Turnaturi R., Parenti C., Pasquinucci L.. Idebenone: Novel Strategies to Improve Its Systemicand Local Efficacy. Nanomaterials. 2018;8:87.Strawser C., Schadt K., Hauser L., McCormick A., Wells M., Larkindale J., Lin H., Lynch D.R. Pharmacological therapeutics in Friedreich ataxia: The present state. Expert Rev. Neurother. 2017;17:895-907.Strawser C., Schadt K., Hauser L., McCormick A., Wells M., Larkindale J., Lin H., Lynch D.R. Pharmacological therapeutics in Friedreich ataxia: The present state. Expert Rev. Neurother. 2017;17:895-907.Fiebiger S.M., Bros H., Grobosch T., Janssen A., Chanvillard C., Paul F., Dorr J., Millward J., Infante-Duarte C. The antioxidant idebenone fails to prevent or attenuate chronic experimental auto-immuneencephalomyelitis in the mouse. J. Neuroimmunol.2013;262:66-71.Fiebiger S.M., Bros H., Grobosch T., Janssen A., Chanvillard C., Paul F., Dorr J., Millward J., Infante-Duarte C. The antioxidant idebenone fails to prevent or attenuate chronic experimental auto-immuneencephalomyelitis in the mouse. J. Neuroimmunol.2013;262:66-71.Yu-Wai-Man P., Soiferman D., Moore D.G., Burte F., Saada A. Evaluating the therapeutic potential ofidebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion. 2017;36:36-42.Yu-Wai-Man P., Soiferman D., Moore D.G., Burte F., Saada A. Evaluating the therapeutic potential ofidebenone and related quinone analogues in Leber hereditary optic neuropathy. Mitochondrion. 2017;36:36-42.Montenegro L., Trapani A., Fini P., Mandracchia D., Latrofa A., Cioffi N., Chiarantini L., Picceri G.G., Brundu S., Puglisi G. Chitosan nanoparticles for topical co-administration of the antioxidants glutathioneand idebenone: Characterization and in vitro release. Br. J. Pharm. Res. 2014;4:2387-2406.Montenegro L., Trapani A., Fini P., Mandracchia D., Latrofa A., Cioffi N., Chiarantini L., Picceri G.G., Brundu S., Puglisi G. Chitosan nanoparticles for topical co-administration of the antioxidants glutathioneand idebenone: Characterization and in vitro release. Br. J. Pharm. Res. 2014;4:2387-2406.

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