sibmedСибирский научный медицинский журналСибирский научный медицинский журнал2410-25122410-2520ИЦиГ СО РАН10.18699/SSMJ20210505sibmed-661Research ArticleМЕДИКО-БИОЛОГИЧЕСКИЕ НАУКИBIOMEDICINEПовышение внутриклеточного уровня НАД+ и разнонаправленные изменения экспрессии CD38 в клетках гиппокампа при экспериментальной болезни АльцгеймераRising of intracellular NAD+ level and oppositely directed changes in CD38 expression in hippocampal cells in experimental Alzheimer’s diseasehttps://orcid.org/0000-0002-2682-8979СемёноваА. А.SemenovaA. A.

Алина Асатовна Семёнова, к.б.н.

660022, г. Красноярск, ул. Партизана Железняка, 1

Alina A. Semenova, candidate of biological sciences

660022, Krasnoyarsk, Partisan Zheleznyak str., 1

alina_shamsutdin@mail.ruhttps://orcid.org/0000-0002-3341-1557ГоринаЯ. В.GorinaYa. V.

Яна Валерьевна Горина, к.фарм.н.

660022, г. Красноярск, ул. Партизана Железняка, 1

Yana V. Gorina, candidate of pharmaceutical sciences

660022, Krasnoyarsk, Partisan Zheleznyak str., 1

 

yana_20@bk.ruhttps://orcid.org/0000-0002-9718-1260ХилажеваЕ. Д.KhilazhevaE. D.

Елена Дмитриевна Хилажева

660022, г. Красноярск, ул. Партизана Железняка, 1

Elena D. Khilazheva

660022, Krasnoyarsk, Partisan Zheleznyak str., 1

elena.hilazheva@mail.ruhttps://orcid.org/0000-0002-1359-9249ХаритоноваЕ. В.KharitonovaE. V.

Екатерина Викторовна Харитонова, к.фарм.н.

660022, г. Красноярск, ул. Партизана Железняка, 1

Ekaterina V. Kharitonova, candidate of pharmaceutical sciences

660022, Krasnoyarsk, Partisan Zheleznyak str., 1

ekaterinav1201@gmail.comhttps://orcid.org/0000-0003-4012-6348СалминаА. Б.SalminaA. B.

Алла Борисовна Салмина, д.м.н., проф.

660022, г. Красноярск, ул. Партизана Железняка, 1;

125367, г. Москва, Волоколамское шоссе, 80

Alla B. Salmina, doctor of medical sciences, professor

660022, Krasnoyarsk, Partisan Zheleznyak str., 1;

125367, Moscow, Volokolamskoe highway, 80

allasalmina@mail.ruКрасноярский государственный медицинский университет имени профессора В.Ф. Войно-Ясенецкого Минздрава РоссииРоссияVoyno-Yasenetsky Krasnoyarsk State Medical University of Minzdrav of RussiaRussian FederationКрасноярский государственный медицинский университет имени профессора В.Ф. Войно-Ясенецкого Минздрава России; Научный центр неврологии Минобрнауки РоссииРоссияVoyno-Yasenetsky Krasnoyarsk State Medical University of Minzdrav of Russia; Research Center of NeurologyRussian Federation2021271020214153746Copyright © Семёнова А.А., Горина Я.В., Хилажева Е.Д., Харитонова Е.В., Салмина А.Б., 20212021Семёнова А.А., Горина Я.В., Хилажева Е.Д., Харитонова Е.В., Салмина А.Б.Semenova A.A., Gorina Y.V., Khilazheva E.D., Kharitonova E.V., Salmina A.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://sibmed.elpub.ru/jour/article/view/661

Целью исследования являлась оценка уровня НАД+ в головном мозге мышей, подвергшихся введению бета-амилоида (Aβ), а также определение активности АДФ-рибозилциклазы/CD38 и количества CD38-иммунопозитивных клеток нейрональной, астроцитарной и эндотелиальной природы. Материал и методы. Модель болезни Альцгеймера воспроизводилась путем интрагиппокампального введения Aβ мышам линии C57BL/6. Содержание НАД+ во внеклеточной жидкости головного мозга и в ткани гиппокампа определяли спектрофотометрически, ферментативную активность АДФ-рибозилциклазы/CD38 – флуориметрическим методом, количество CD38-иммунопозитивных клеток – методом иммуногистохимии. Результаты и их обсуждение. Уровень НАД+ был значительно повышен в ткани гиппокампа у мышей после введения Aβ, при этом концентрация внеклеточного НАД+ не изменялась. Активность АДФ-рибозилциклазы/CD38 в ткани гиппокампа осталось прежним, однако число CD38-иммунопозитивных нейронов снизилось, а количество CD38+ эндотелиоцитов увеличилось в гиппокампе мышей после введения Aβ. Заключение. Разнонаправленные изменения экспрессии АДФ-рибозилциклазы/CD38 в нейронах и эндотелиоцитах соответствуют разному метаболическому состоянию этих  типов клеток и наряду с увеличением внутриклеточного пула НАД+ при экспериментальной болезни Альцгеймера отражают адаптивный стрессовый ответ на введение Aβ.

The aim of the study was to assess the level of NAD+ in the brain of mice treated with beta-amyloid (Aβ), as well as to determine the activity of ADP-ribosyl cyclase/CD38 and the number of CD38-immunopositive neurons, astrocytes and endothelial cells. Material and methods. The Alzheimer’s disease model was reproduced by intrahippocampal administration of Aβ to C57BL/6 mice. Determination of the NAD+ level in the extracellular fluid of the brain and in the hippocampal tissue was carried out by spectrophotometric analysis. Evaluation of the enzymatic activity of ADP-ribosyl cyclase / CD38 was carried out by the fluorimetric method, determination of the number of CD38-immunopositive cells by the immunohistochemistry method. Results and discussion. The level of NAD+ was significantly increased in the hippocampal tissue in mice after administration of Aβ, while the level of extracellular NAD+ did not change. The activity of ADP-ribosyl cyclase / CD38 in the hippocampal tissue did not change, but the number of CD38-immunopositive neurons decreased, and the number of CD38+ endothelial cells increased in the hippocampus of mice after administration of Aβ. Conclusion. Opposite changes in the expression of ADP-ribosyl cyclase / CD38 in neurons and endotheliocytes correspond to different metabolic states of these types of cells and, along with an increased intracellular pool of NAD+ in experimental Alzheimer’s disease, reflect an adaptive stress response to Aβ administration.

болезнь Альцгеймерабета-амилоидангиопатияНАД+CD38Alzheimer’s diseasebeta amyloidangiopathyNAD+CD38Работа выполнена при государственной финансовой поддержке Президента РФ ведущих научных школ РФ (проект НШ-2547.2020.7) на базе НИИ молекулярной медицины и патобиохимии, с использованием оборудования ЦКП «Молекулярные и клеточные технологии».This work was carried out with the state financial support of the President of the Russian Federation of the leading scientific schools of the Russian Federation (project NSh-2547.2020.7) on the basis of the Research Institute of Molecular Medicine and Pathobiochemistry using equipment from the Center for Collective Use «Molecular and Cellular Technologies».ReferencesKurakin A., Bredesen D.E. Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics. Aging (Albany NY). 2020; 12 (18): 17815–17844. doi: 10.18632/aging.103883Kurakin A., Bredesen D.E. Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics. Aging (Albany NY). 2020; 12 (18): 17815–17844. doi: 10.18632/aging.103883Fernandez-Fernandez S., Almeida A., Bolaños J.P. Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 2012; 443 (1): 3–11. doi: 10.1042/BJ20111943Fernandez-Fernandez S., Almeida A., Bolaños J.P. Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 2012; 443 (1): 3–11. doi: 10.1042/BJ20111943Kerr J.S., Adriaanse B.A., Greig N.H., Mattson M.P., Cader M.Z., Bohr V.A., Fang E.F.. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci. 2017; 40 (3): 151–166. doi: 10.1016/j.tins.2017.01.002Kerr J.S., Adriaanse B.A., Greig N.H., Mattson M.P., Cader M.Z., Bohr V.A., Fang E.F.. Mitophagy and Alzheimer’s disease: cellular and molecular mechanisms. Trends Neurosci. 2017; 40 (3): 151–166. doi: 10.1016/j.tins.2017.01.002Rose J., Brian C., Woods J., Pappa A., Panayiotidis M.I., Powers R., Franco R. Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival. Toxicology. 2017; 391: 109–115. doi: 10.1016/j.tox.2017.06.011Rose J., Brian C., Woods J., Pappa A., Panayiotidis M.I., Powers R., Franco R. Mitochondrial dysfunction in glial cells: Implications for neuronal homeostasis and survival. Toxicology. 2017; 391: 109–115. doi: 10.1016/j.tox.2017.06.011Dong Y., Brewer G.J. Global metabolic shifts in age and alzheimer’s disease mouse brains pivot at NAD+/NADH redox sites. J. Alzheimers Dis. 2019; 71 (1): 119–140. doi: 10.3233/JAD-190408Dong Y., Brewer G.J. Global metabolic shifts in age and alzheimer’s disease mouse brains pivot at NAD+/NADH redox sites. J. Alzheimers Dis. 2019; 71 (1): 119–140. doi: 10.3233/JAD-190408Katsyuba E., Romani M., Hofer D., Auwerx J. NAD+ homeostasis in health and disease. Nat. Metab. 2020; 2 (1): 9–31. doi: 10.1038/s42255-019-0161-5Katsyuba E., Romani M., Hofer D., Auwerx J. NAD+ homeostasis in health and disease. Nat. Metab. 2020; 2 (1): 9–31. doi: 10.1038/s42255-019-0161-5Camacho-Pereira J., Tarragó M.G., Chini C.C.S., Nin V., Escande C., Warner G.M., Puranik A.S., Schoon R.A., Reid J.M., Galina A., Chini E.N. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an sirt3-dependent mechanism. Cell Metab. 2016; 23 (6): 1127–1139. doi: 10.1016/j.cmet.2016.05.006Camacho-Pereira J., Tarragó M.G., Chini C.C.S., Nin V., Escande C., Warner G.M., Puranik A.S., Schoon R.A., Reid J.M., Galina A., Chini E.N. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an sirt3-dependent mechanism. Cell Metab. 2016; 23 (6): 1127–1139. doi: 10.1016/j.cmet.2016.05.006Chini E.N. CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr. Pharm. Des. 2009; 15 (1): 57–63. doi: 10.2174/138161209787185788Chini E.N. CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr. Pharm. Des. 2009; 15 (1): 57–63. doi: 10.2174/138161209787185788Horenstein A.L., Faini A.C., Morandi F., Bracci C., Lanza F., Giuliani N., Paulus A., Malavasi F. The circular life of human cd38: from basic science to clinics and back. Molecules. 2020; 25 (20): 4844. doi: 10.3390/molecules25204844Horenstein A.L., Faini A.C., Morandi F., Bracci C., Lanza F., Giuliani N., Paulus A., Malavasi F. The circular life of human cd38: from basic science to clinics and back. Molecules. 2020; 25 (20): 4844. doi: 10.3390/molecules25204844Салмина А.Б., Инжутова А.И., Моргун А.В., Окунева О.С., Малиновская Н.А., Лопатина О.Л., Петрова М.М., Таранушенко Т.Е., Фурсов А.А., Кувачева Н.В. НАД+-конвертирующие ферменты в клетках нейрональной и глиальной природы: СD38 как новая молекула-мишень для нейропротекции. Вестн. РАМН. 2019; 67 (10): 29–37. doi: 10.15690/vramn.v67i10.413Salmina A.B., Inzhutova A.I., Morgun A.V., Okuneva O.S., Malinovskaya N.A., Lopatina O.L., Petrova M.M., Taranushenko T.E., Fursov A.A., Kuvacheva N.V. NAD+-converting enzymes in neuronal and glial cells: CD38 as a novel target for neuroprotection. Vestnik Rossiiskoy akademii meditsinskikh nauk = Annals of the Russian Academy of Medical Sciences. 2012; 67 (10): 29–37. [In Russian]. doi: 10.15690/vramn.v67i10.413Aksoy P., White T.A., Thompson M., Chini E.N. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem. Biophys. Res. Commun. 2006; 345 (4): 1386–1392. doi: 10.1016/j.bbrc.2006.05.042Aksoy P., White T.A., Thompson M., Chini E.N. Regulation of intracellular levels of NAD: a novel role for CD38. Biochem. Biophys. Res. Commun. 2006; 345 (4): 1386–1392. doi: 10.1016/j.bbrc.2006.05.042Deaglio S., Morra M., Mallone R., Ausiello C.M., Prager E., Garbarino G., Dianzani U., Stockinger H., Malavasi F. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 1998; 160 (1): 395–402.Deaglio S., Morra M., Mallone R., Ausiello C.M., Prager E., Garbarino G., Dianzani U., Stockinger H., Malavasi F. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J. Immunol. 1998; 160 (1): 395–402.Higashida H., Salmina A.B., Olovyannikova R.Y., Hashii M., Yokoyama S., Koizumi K., Jin D., Liu H.X., Lopatina O., Amina S., Islam M.S., Huang J.J., Noda M. Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system. Neurochem. Int. 2007; 51 (2-4): 192–199. doi: 10.1016/j.neuint.2007.06.023Higashida H., Salmina A.B., Olovyannikova R.Y., Hashii M., Yokoyama S., Koizumi K., Jin D., Liu H.X., Lopatina O., Amina S., Islam M.S., Huang J.J., Noda M. Cyclic ADP-ribose as a universal calcium signal molecule in the nervous system. Neurochem. Int. 2007; 51 (2-4): 192–199. doi: 10.1016/j.neuint.2007.06.023Deaglio S., Mallone R., Baj G., Arnulfo A., Surico N., Dianzani U., Mehta K., Malavasi F. CD38/CD31, a receptor/ligand system ruling adhesion and signaling in human leukocytes. Chem. Immunol. 2000; 75: 99–120.Deaglio S., Mallone R., Baj G., Arnulfo A., Surico N., Dianzani U., Mehta K., Malavasi F. CD38/ CD31, a receptor/ligand system ruling adhesion and signaling in human leukocytes. Chem. Immunol. 2000; 75: 99–120.Malavasi F., Deaglio S., Funaro A., Ferrero E., Horenstein A.L., Ortolan E., Vaisitti T., Aydin S. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol. Rev. 2008; 88 (3): 841–886. doi: 10.1152/physrev.00035.2007Malavasi F., Deaglio S., Funaro A., Ferrero E., Horenstein A.L., Ortolan E., Vaisitti T., Aydin S. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol. Rev. 2008; 88 (3): 841–886. doi: 10.1152/physrev.00035.2007Franco L., Guida L., Bruzzone S., Zocchi E., Usai C., de Flora A. The transmembrane glycoprotein CD38 is a catalytically active transporter responsible for generation and influx of the second messenger cyclic ADP-ribose across membranes. FASEB J. 1998; 12 (14): 1507–1520. doi: 10.1096/fasebj.12.14.1507Franco L., Guida L., Bruzzone S., Zocchi E., Usai C., de Flora A. The transmembrane glycoprotein CD38 is a catalytically active transporter responsible for generation and influx of the second messenger cyclic ADP-ribose across membranes. FASEB J. 1998; 12 (14): 1507–1520. doi: 10.1096/fasebj.12.14.1507Song E.K., Rah S.Y., Lee Y.R., Yoo C.H., Kim Y.R., Yeom J.H., Park K.H., Kim J.S., Kim U.H., Han M.K. Connexin-43 hemichannels mediate cyclic ADP-ribose generation and its Ca2+-mobilizing activity by NAD+/cyclic ADP-ribose transport. J. Biol.Chem. 2011; 286 (52): 44480–44490. doi: 10.1074/jbc.M111.307645Song E.K., Rah S.Y., Lee Y.R., Yoo C.H., Kim Y.R., Yeom J.H., Park K.H., Kim J.S., Kim U.H., Han M.K. Connexin-43 hemichannels mediate cyclic ADP-ribose generation and its Ca2+-mobilizing activity by NAD+/cyclic ADP-ribose transport. J. Biol.Chem. 2011; 286 (52): 44480–44490. doi: 10.1074/jbc.M111.307645Hayakawa K., Esposito E., Wang X., Terasaki Y., Liu Y., Xing C., Ji X., Lo E.H. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535 (7613): 551–555. doi: 10.1038/nature18928Hayakawa K., Esposito E., Wang X., Terasaki Y., Liu Y., Xing C., Ji X., Lo E.H. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535 (7613): 551–555. doi: 10.1038/nature18928Guerreiro S., Privat A.L., Bressac L., Toulorge D. CD38 in neurodegeneration and neuroinflammation. Cells. 2020; 9 (2): 471. doi: 10.3390/cells9020471Guerreiro S., Privat A.L., Bressac L., Toulorge D. CD38 in neurodegeneration and neuroinflammation. Cells. 2020; 9 (2): 471. doi: 10.3390/cells9020471Boslett J., Hemann C., Christofi F.L., Zweier J.L. Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion. Am. J. Physiol. Cell Physiol. 2018; 314 (3): 297–309. doi: 10.1152/ajpcell.00139.2017Boslett J., Hemann C., Christofi F.L., Zweier J.L. Characterization of CD38 in the major cell types of the heart: endothelial cells highly express CD38 with activation by hypoxia-reoxygenation triggering NAD(P)H depletion. Am. J. Physiol. Cell Physiol. 2018; 314 (3): 297–309. doi: 10.1152/ajpcell.00139.2017Epelbaum S., Youssef I., Lacor P.N., Chaurand P., Duplus E., Brugg B., Duyckaerts C., Delatour B. Acute amnestic encephalopathy in amyloid-β oligomer-injected mice is due to their widespread diffusion in vivo. Neurobiol. Aging. 2015; 36 (6): 2043– 2052. doi: 10.1016/j.neurobiolaging.2015.03.005Epelbaum S., Youssef I., Lacor P.N., Chaurand P., Duplus E., Brugg B., Duyckaerts C., Delatour B. Acute amnestic encephalopathy in amyloid-β oligomer-injected mice is due to their widespread diffusion in vivo. Neurobiol. Aging. 2015; 36 (6): 2043–2052. doi: 10.1016/j.neurobiolaging.2015.03.005Sipos E., Kurunczi A., Kasza A., Horvath J., Felszeghy K., Laroche S., Toldi J., Parducz A., Penke B., Penke Z. Beta-amyloid pathology in the entorhinal cortex of rats induces memory deficits: implications for Alzheimer’s disease. Neuroscience. 2007; 147 (1): 28–36. doi: 10.1016/j.neuroscience.2007.04.011Sipos E., Kurunczi A., Kasza A., Horvath J., Felszeghy K., Laroche S., Toldi J., Parducz A., Penke B., Penke Z. Beta-amyloid pathology in the entorhinal cortex of rats induces memory deficits: implications for Alzheimer’s disease. Neuroscience. 2007; 147 (1): 28–36. doi: 10.1016/j.neuroscience.2007.04.011Encinas J.M., Enikolopov G. Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol. 2008; 85C: 243–272. doi: 10.1016/S0091-679X(08)85011-XEncinas J.M., Enikolopov G. Identifying and quantitating neural stem and progenitor cells in the adult brain. Methods Cell Biol. 2008; 85C: 243–272. doi: 10.1016/S0091-679X(08)85011-XZhu X.H., Lu M., Lee B.Y., Ugurbil K., Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl. Acad. Sci. USA. 2015; 112 (9): 2876–2881. doi: 10.1073/pnas.1417921112Zhu X.H., Lu M., Lee B.Y., Ugurbil K., Chen W. In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences. Proc. Natl. Acad. Sci. USA. 2015; 112 (9): 2876–2881. doi: 10.1073/pnas.1417921112Xie N., Zhang L., Gao W., Huang C., Huber P.E., Zhou X., Li C., Shen G., Zou B. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct. Target Ther. 2020; 5 (1): 227. doi: 10.1038/s41392-020-00311-7Xie N., Zhang L., Gao W., Huang C., Huber P.E., Zhou X., Li C., Shen G., Zou B. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct. Target Ther. 2020; 5 (1): 227. doi: 10.1038/s41392-020-00311-7Luengo A., Li Z., Gui D.Y., Sullivan L.B., Zagorulya M., Do B.T., Ferreira R., Naamati A., Ali A., Lewis C.A., Thomas C.J., Spranger S., Matheson N.J., Vander Heiden M.G. Increased demand for NAD+ relative to ATP drives aerobic glycolysis. Mol. Cell. 2021; 81 (4): 691–707. doi: 10.1016/j.molcel.2020.12.012Luengo A., Li Z., Gui D.Y., Sullivan L.B., Zagorulya M., Do B.T., Ferreira R., Naamati A., Ali A., Lewis C.A., Thomas C.J., Spranger S., Matheson N.J., Vander Heiden M.G. Increased demand for NAD+ relative to ATP drives aerobic glycolysis. Mol. Cell. 2021; 81 (4): 691–707. doi: 10.1016/j.molcel.2020.12.012Braidy N., Berg J., Clement J., Khorshidi F., Poljak A., Jayasena T., Grant R., Sachdev P. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid. Redox Signal. 2019; 30 (2): 251–294. doi: 10.1089/ars.2017.7269Braidy N., Berg J., Clement J., Khorshidi F., Poljak A., Jayasena T., Grant R., Sachdev P. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age-related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid. Redox Signal. 2019; 30 (2): 251–294. doi: 10.1089/ars.2017.7269Mills K.F., Yoshida S., Stein L.R., Grozio A., Kubota S., Sasaki Y., Redpath P., Migaud M.E., Apte R.S., Uchida K., Yoshino J., Imai S.I. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016; 24 (6): 795–806. doi: 10.1016/j.cmet.2016.09.013Mills K.F., Yoshida S., Stein L.R., Grozio A., Kubota S., Sasaki Y., Redpath P., Migaud M.E., Apte R.S., Uchida K., Yoshino J., Imai S.I. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016; 24 (6): 795–806. doi: 10.1016/j.cmet.2016.09.013Wang X., Hu X., Yang Y., Takata T., Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016; 1643: 1–9. doi: 10.1016/j.brainres.2016.04.060Wang X., Hu X., Yang Y., Takata T., Sakurai T. Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death. Brain Res. 2016; 1643: 1–9. doi: 10.1016/j.brainres.2016.04.060Gerasimenko M., Cherepanov S.M., Furuhara K., Lopatina O., Salmina A.B., Shabalova A.A., Tsuji C., Yokoyama S., Ishihara K., Brenner C., Higashida H. Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder. Sci. Rep. 2020; 10 (1): 10035. doi: 10.1038/s41598-019-57236-7Gerasimenko M., Cherepanov S.M., Furuhara K., Lopatina O., Salmina A.B., Shabalova A.A., Tsuji C., Yokoyama S., Ishihara K., Brenner C., Higashida H. Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder. Sci. Rep. 2020; 10 (1): 10035. doi: 10.1038/s41598-019-57236-7Choi J.E., Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr. Opin Genet. Dev. 2014; 26: 24–32. doi: 10.1016/j.gde.2014.05.005Choi J.E., Mostoslavsky R. Sirtuins, metabolism, and DNA repair. Curr. Opin Genet. Dev. 2014; 26: 24–32. doi: 10.1016/j.gde.2014.05.005Bruzzone S., Guida L., Zocchi E., Franco L., de Flora A. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J. 2001; 15 (1): 10–12. doi: 10.1096/fj.00-0566fjeBruzzone S., Guida L., Zocchi E., Franco L., de Flora A. Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells. FASEB J. 2001; 15 (1): 10–12. doi: 10.1096/fj.00-0566fjeClement J., Wong M., Poljak A., Sachdev P., Braidy N. The plasma NAD+ metabolome is dysregulated in «normal» aging. Rejuvenation Res. 2019; 22 (2): 121–130. doi: 10.1089/rej.2018.2077Clement J., Wong M., Poljak A., Sachdev P., Braidy N. The plasma NAD+ metabolome is dysregulated in «normal» aging. Rejuvenation Res. 2019; 22 (2): 121–130. doi: 10.1089/rej.2018.2077Billington R.A., Travelli C., Ercolano E., Galli U., Roman C.B., Grolla A.A., Canonico P.L., Condorelli F., Genazzani A.A. Characterization of NAD uptake in mammalian cells. J. Biol. Chem. 2008; 283 (10): 6367–6374. doi: 10.1074/jbc.M706204200Billington R.A., Travelli C., Ercolano E., Galli U., Roman C.B., Grolla A.A., Canonico P.L., Condorelli F., Genazzani A.A. Characterization of NAD uptake in mammalian cells. J. Biol. Chem. 2008; 283 (10): 6367–6374. doi: 10.1074/jbc.M706204200Leung S.W.S., Shi Y. The glycolytic process in endothelial cells and its implications. Acta Pharmacol. Sin. 2021. doi: 10.1038/s41401-021-00647-yLeung S.W.S., Shi Y. The glycolytic process in endothelial cells and its implications. Acta Pharmacol. Sin. 2021. doi: 10.1038/s41401-021-00647-ySalmina A.B., Kuvacheva N.V., Morgun A.V., Komleva Y.K., Pozhilenkova E.A., Lopatina O.L., Gorina Y.V., Taranushenko T.E., Petrova L.L. Glycolysis-mediated control of blood-brain barrier development and function. Int. J. Biochem. Cell Biol. 2015; 64: 174–184. doi: 10.1016/j.biocel.2015.04.005Salmina A.B., Kuvacheva N.V., Morgun A.V., Komleva Y.K., Pozhilenkova E.A., Lopatina O.L., Gorina Y.V., Taranushenko T.E., Petrova L.L. Glycolysis- mediated control of blood-brain barrier development and function. Int. J. Biochem. Cell Biol. 2015; 64: 174–184. doi: 10.1016/j.biocel.2015.04.005

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