ssmuБюллетень сибирской медициныBulletin of Siberian Medicine1682-03631819-3684Siberian State Medical University, the Ministry of Healthcare of the Russian Federation10.20538/1682-0363-2017-4-106-115ssmu-1028Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSВлияние инсулинорезистентности на нарушение метаболизма глюкозы в миндалине головного мозга при экспериментальной болезни АльцгеймераThe effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s diseaseГоринаЯ. В.GorinaYa. V.

канд. фарм. наук, доцент

кафедра биохимии с курсами медицинской, фармацевтической и токсикологической химии

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

PhD, Associate Professor, Department of Biological Chemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry

1, Partizan Zheleznyak Str., Krasnoyarsk, 660022

yana_20@bk.ruКомлеваЮ. К.KomlevaYu. K.

канд. мед. наук, доцент

кафедра биохимии с курсами медицинской, фармацевтической и токсикологической химии

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

PhD, Associate Professor, Department of Biological Chemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry

1, Partizan Zheleznyak Str., Krasnoyarsk, 660022

ЛопатинаО. Л.LopatinaO. L.

канд. биол. наук, доцент

кафедра биохимии с курсами медицинской, фармацевтической и токсикологической химии

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

PhD, Associate Professor, Department of Biological Chemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry

1, Partizan Zheleznyak Str., Krasnoyarsk, 660022

ЧерныхА. И.ChernykhA. I.

врач-хирург

660123, г. Красноярск, ул. Инструментальная, 12А 

Surgeon

12A, Instrumental Str., Krasnoyarsk, 660123

СалминаА. Б.SalminaA. B.

д-р мед. наук, профессор, зав. кафедрой биохимии с курсами медицинской, фармацевтической и токсикологической химии, руководитель

НИИ молекулярной медицины и патобиохимии

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

DM, Professor, Head of the Department of Biological Chemistry with Courses of Medical, Pharmaceutical and Toxicological Chemistry, Head

Research Institute of Molecular Medicine and Pathological Biochemistry

1, Partizan Zheleznyak Str., Krasnoyarsk, 660022

Красноярский государственный медицинский университет (КГМУ) имени профессора В.Ф. Войно-ЯсенецкогоРоссияKrasnoyarsk State Medical University (KSMU) named after Prof. V.F. Voino-YasenetskyRussian FederationКрасноярская межрайонная клиническая больница № 20 им. И.С. БерзонаРоссияKrasnoyarsk Interdistrict Clinical Hospital № 20 named after I.S. BerzonRussian Federation201702012018164106115Copyright © Горина Я.В., Комлева Ю.К., Лопатина О.Л., Черных А.И., Салмина А.Б., 20182018Горина Я.В., Комлева Ю.К., Лопатина О.Л., Черных А.И., Салмина А.Б.Gorina Y.V., Komleva Y.K., Lopatina O.L., Chernykh A.I., 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://bulletin.ssmu.ru/jour/article/view/1028Цель

Цель. В головном мозге метаболизм глюкозы четко регулируется, поэтому его нарушение является важной особенностью нейродегенеративных заболеваний, в частности болезни Альцгеймера. Транспорт глюкозы в мембрану клетки реализуется за счет активности инсулин-регулируемой аминопептидазы (IRAP), которая влияет на память и обучение, и рассматривается как один из ключевых маркеров инсулинорезистентности при болезни Альцгеймера. Однако вопрос о механизме действия IRAP остается открытым. Цель исследования – изучение влияния экспрессии IRAP на клетках нейрональной и глиальной природы, а также совместно с инсулинзависимым глюкозным транспортером (GLUT4) в миндалине головного мозга на эмоциональную память у животных с экспериментальной болезнью Альцгеймера.

Материал и методы

Материал и методы. Исследование проводили на животных с использованием двух экспериментальных моделей болезни Альцгеймера – инъекционной и генетической. Опытная группа – мыши линии CD1, самцы в возрасте 4 мес, которым билатерально вводили бета-амилоид 1-42 в зону гиппокампа CA1 (сornu аmmonis)по 1 мкл. Контрольная группа – мыши линии CD1, самцы в возрасте 4 мес, которым билатерально вводили растворитель для бета-амилоида – фосфатно-солевой буфер в зону CA1 по 1 мкл.

Генетическая модель болезни Альцгеймера – мыши линии B6SLJ –Tg(APPSwFlLon,PSEN1*M146L*L286 V)6799Vas, самцы в возрасте 4 мес. Контрольная группа – мыши линии C57BL/6xSJL, самцы в возрасте 4 мес. Оценку эмоциональной памяти проводили с использованием нейроповеденческого тестирования Fear conditioning. Экспрессию молекул-маркеров инсулинорезистентности в миндалине изучали методом иммуногистохимии с последующей конфокальной микроскопией.

Результаты

Результаты. У животных с экспериментальной моделью болезни Альцгеймера выявлено нарушение ассоциативного обучения и эмоциональной памяти. Выявлено снижение (р ≤ 0,05) экспрессии IRAP на клетках нейрональной и глиальной природы, а также (совместно с GLUT4) в миндалине головного мозга у животных с экспериментальной болезнью Альцгеймера.

Заключение

Заключение. Уменьшение числа IRAP-иммунопозитивных нейрональных и астроглиальных клеток, а также экспрессии IRAP/GLUT4 в клетках миндалины у животных с экспериментальной моделью болезни Альцгеймера указывает на развитие инсулинорезистентности в миндалине головного мозга, находящейся во взаимосвязи с гиппокампом при осуществлении когнитивных функций и запоминания, сопряженных с эмоционально окрашенными событиями. 

Purpose

Purpose. Glucose metabolism is tightly regulated in the brain. Aberrant glucose metabolism is an important feature of neurodegenerative diseases, as inAlzheimer’s disease. The transport of glucose to the cell membrane is realized through the activity of insulin-regulated aminopeptidase (IRAP) which controls transfer of glucose transporter to the plasma membrane. IRAP is considered as one of the key markers of insulin resistance in Alzheimer’s disease. However, the question of the mechanism of the action of the IRAP remains open. The aim of the study was to study the effect of IRAP expression on cells of the neuronal and glial lineage, glucose transporter (GLUT4) expression in the brain amygdala on emotional memory in animals with experimental Alzheimer’s disease.

Materials and methods

Materials and methods. The study was performed with two experimental models of Alzheimer’s disease in mice. The experimental group was mice of the CD1 line, males aged 4 months (Alzheimer’s disease model with the intra-hippocampal administration of beta-amyloid 1-42 (1 µl) bilaterally in the CA1 area). The control group was mice of the CD1 line, males aged 4 months (sham-operated animals with the intrahippocampal administration of Phosphate buffered salin (1 µl) bilaterally in the CA1). The genetic model of Alzheimer’s disease is the B6SLJ-Tg line mice (APPSwFlLon, PSEN1*M146L*L286V) 6799Vas, males aged 4 months. The control group consisted of C57BL/6xSJL mice, males aged 4 months. Evaluation of emotional memory was carried out using “Fear conditioning” protocol. Expression of molecule-markers of insulin-resistance in the amygdala was studied by immunohistochemistry followed by confocal microscopy.

Results

Results. Aberrant associative learning and emotional memory was revealed in animals with an experimental model of Alzheimer’s disease. A decrease (p ≤ 0,05) of IRAP expression on cells of neuronal and glial nature, associated with GLUT4 down-regulation was detected in amygdala of brain in animals with experimental Alzheimer’s disease.

Conclusion

Conclusion. Decreased number of IRAP-immunopositive neuronal and astroglial cells, as well as IRAP+/ GLUT4+ in cells of amygdala in animals with an experimental model of Alzheimer’s disease, indicates the development of insulin resistance in amygdala of brain, which was in correlation with the hippocampus in performing cognitive functions and memorizing associated with emotionally colored events. 

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