mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2018-3-303-312mimmun-1543Research ArticleОБЗОРЫREVIEWSПОЛИМОРФИЗМ ГЕНА АРОЕ: ВЛИЯНИЕ АЛЛЕЛЯ APOE4 НА СИСТЕМНОЕ ВОСПАЛЕНИЕ И ЕГО РОЛЬ В ПАТОГЕНЕЗЕ БОЛЕЗНИ АЛЬЦГЕЙМЕРАAPOE GENE POLYMORPHISM: THE IMPACT OF APOE4 ALLELE ON SYSTEMIC INFLAMMATION AND ITS ROLE IN THE PATHOGENESIS OF ALZHEIMER’S DISEASEМалашенковаИ. К.MalashenkovaI. K.

Кандидат медицинских наук, начальник лаборатории иммунологии и вирусологии НИЦ «Курчатовский институт»; лаборатория клинической иммунологии ФНКЦФМ ФМБА России.

Москва

PhD (Medicine), Head, Laboratory of Immunology and Virology NRC “Kurchatov Institute”; Laboratory of Clinical Immunology, Federal Clinical Research Center of Physical-Chemical Medicine, Federal Medical-Biological Agency.

Moscow

КрынскийС. А.KrynskiyS. A.

Крынский Сергей Андреевич – младший научный сотрудник лаборатории иммунологии и вирусологии, НИЦ «Курчатовский институт»; лаборатория клинической иммунологии ФНКЦФМ ФМБА России.

123182, Москва,  площадь академика Курчатова, 1, тел.: 8 (499) 196-95-39, факс: 8 (499) 196-17-04

Krynskiy Sergey A. - Junior Research Associate, Laboratory of Immunology and Virology NRC “Kurchatov Institute”; Laboratory of Clinical Immunology, FCRC Physical-Chemical Medicine FMBA.

123182, Moscow, Acad. Kurchatov Square, 1, phone: 7 (499) 196-95-39, fax: 7 (499) 196-17-04

srgkr002@gmail.comМамошинаМ. В.MamoshinaM. V.

Студент, лаборатория иммунологии и вирусологии НИЦ «Курчатовский институт»

Student, Laboratory of Immunology and Virology NRC “Kurchatov Institute”

ДидковскийН. А.DidkovskiyN. A.

Доктор медицинских наук, профессор, заведующий лабораторией клинической иммунологии.

Москва

PhD, MD (Medicine), Professor, Head, Laboratory of Clinical Immunology, FCRC Physical-Chemical Medicine FMBA.

Moscow

Национальный исследовательский центр «Курчатовский институт»; ФГБУ Федеральный научно-клинический центр физико-химической медицины ФМБА РоссииРоссияNational Research Center “Kurchatov Institute”; Federal Clinical Research Center of Physical-Chemical Medicine, Federal Medical-Biological AgencyRussian FederationНациональный исследовательский центр «Курчатовский институт»; ФГАОУ ВО Московский физико-технический институт (государственный университет)РоссияNational Research Center “Kurchatov Institute”; Moscow Institute of Physics and Technology (The State University)Russian FederationФГБУ Федеральный научно-клинический центр физико-химической медицины ФМБА РоссииРоссияFederal Clinical Research Center of Physical-Chemical Medicine, Federal Medical-Biological AgencyRussian Federation201811062018203303312Copyright © Малашенкова И.К., Крынский С.А., Мамошина М.В., Дидковский Н.А., 20182018Малашенкова И.К., Крынский С.А., Мамошина М.В., Дидковский Н.А.Malashenkova I.K., Krynskiy S.A., Mamoshina M.V., Didkovskiy N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/1543

ApoE – белок семейства липопротеинов, наиболее высокий уровень его экспрессии отмечается в печени и в центральной нервной системе (ЦНС). ApoE секретируется астроцитами, микроглией, нейронами, а также иммунокомпетентными клетками, включая лимфоциты, моноциты и макрофаги. Согласно данным последних лет, этот белок, помимо участия в обмене липидов в ЦНС, имеет эндотелиотропные функции (индуцирует синтез NO-синтазы, уменьшает адгезию моноцитов к эндотелию), а также оказывает иммуномодулируюшее действие: подавляет воспалительную активацию фагоцитов и антиген-стимулированную пролиферацию Т-клеток. Полиморфный аллель APOE4 гена APOE – основной генетический фактор риска болезни Альцгеймера, повышающий вероятность заболевания более чем в 3 раза. Белок, кодируемый данным аллелем, имеет измененную функциональную активность. Механизмы, способствующие более раннему развитию нейродегенерации у носителей полиморфизма, связаны с рядом факторов, среди которых нарушение обмена липидов в ЦНС, предрасположенность к формированию нейротоксичных олигомеров амилоида-бета, замедленный клиренс амилоида-бета из ЦНС, нарушение регуляции иммунных процессов в ЦНС. В настоящем обзоре рассматриваются современные представления о функциях белка ApoE в центральной нервной системе и иммунной системе, описываются изменения функциональной активности белка у носителей аллеля APOE4. Приводятся данные о влиянии полиморфизма гена APOE на фенотип моноцитов человека и их воспалительную активацию, метаболизм амилоида-бета, на специфический клеточный ответ к антигенам амилоида-бета и на проявления нейровоспаления при болезни Альцгеймера. Обсуждается возможное участие иммунотропных эффектов ApoE в формировании повышенного риска болезни Альцгеймера, характерного для носителей APOE4.

ApoE is a member of lipoprotein family. It is the most common lipoprotein in the central nervous system (CNS), secreted by astrocytes, microglia, neurons and immunocompetent cells, including lymphocytes, monocytes and macrophages. According to recent data, it has endotheliotropic and immunomodulatory functions, regulating inflammatory activation of mononuclear phagocytes and antigen-induced lymphocyte proliferation. APOE4  allele is a major genetic risk factor of Alzheimer’s disease, with prevalence 3-12 times higher in those who have this allele. Mechanisms that predispose carriers of the allele to earlier clinical presentation of neurodegeneration include changes in lipid metabolism in the CNS, in the buildup of neurotoxic amyloid-beta oligomers, in the clearance of amyloid-beta peptides from the CNS and in regulation of immune response. In this review the functions of ApoE protein in central nervous and immune system and changes in functional activity of the protein in APOE4 carriers are discussed. The impact of APOE4 allele on monocyte phenotype and inflammatory activation of monocytes, on specific cell-mediated immune response to amyloid-beta antigens and on effectiveness of immunomodulatory therapy in patients with Alzheimer’s disease summarized, as well as the possible role of changes in the immune response characteristic for APOE4 carriers in the increased risk of Alzheimer’s disease.

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