vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-45vavilov-4182Research ArticleРЕПРОДУКТИВНЫЕ ТЕХНОЛОГИИPHYSIOLOGICAL GENETICSДействие амисульприда на экспрессию серотониновых рецепторов, нейротрофического фактора BDNF и его рецепторов при сверхэкспрессии склонного к агрегации тау-белка с мутацией [R406W] у мышейEffect of amisulpride on the expression of serotonin receptors, neurotrophic factor BDNF and its receptors in mice with overexpression of the aggregation-prone [R406W] mutant tau proteinhttps://orcid.org/0000-0002-0542-4481КондауроваЕ. М.KondaurovaE. M.

Новосибирск 

Novosibirsk 

kond_em@bionet.nsc.ruКомароваА. А.KomarovaA. A.

Новосибирск 

Novosibirsk 

https://orcid.org/0000-0002-1816-4084ИльчибаеваТ. В.IlchibaevaT. V.

Новосибирск 

Novosibirsk 

https://orcid.org/0000-0001-5739-4176РодныйА. Я.RodnyyA. Ya.

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Novosibirsk 

ЗаливинаЕ. А.ZalivinaE. A.

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Novosibirsk 

https://orcid.org/0000-0001-7196-4729НауменкоВ. С.NaumenkoV. S.

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Novosibirsk 

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202411072024284398406Copyright © Кондаурова Е.М., Комарова А.А., Ильчибаева Т.В., Родный А.Я., Заливина Е.А., Науменко В.С., 20242024Кондаурова Е.М., Комарова А.А., Ильчибаева Т.В., Родный А.Я., Заливина Е.А., Науменко В.С.Kondaurova E.M., Komarova A.A., Ilchibaeva T.V., Rodnyy A.Y., Zalivina E.A., Naumenko V.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4182

Серотониновые рецепторы 5-HT7 (5-HT7R) привлекают все больше внимания в качестве одного из важных звеньев в механизмах развития болезни Альцгеймера и возможной мишени для лечения различных тау-патологий. В настоящей работе исследовано влияние амисульприда (обратный агонист 5-HT7R) в модели экспериментального повышения экспрессии гена, кодирующего склонный к агрегации белок человека Tau[R406W], в префронтальной коре мышей линии C57BL/6J на кратковременную память и экспрессию генов, участвующих в развитии таупатии (Htr7 и Cdk5), а также биомаркеров нейродегенеративных процессов – гена Bdnf и его рецепторов TrkB (ген Ntrk2) и p75NTR (ген Ngfr). В тесте на кратковременную память мыши не было обнаружено разницы по индексу дискриминации между мышами, которым вводили AAV-Tau[R406W], и мышами с AAV-EGFP. Амисульприд не повлиял на данный показатель. Введение AAV-Tau[R406W] привело к повышению экспрессии генов Htr7, Htr1a и Cdk5 в префронтальной коре по сравнению с животными группы AAV-EGFP. При этом амисульприд в дозе 10 мг/кг у животных группы AAV-Tau[R406W] вызвал снижение уровня мРНК генов Htr7 и Htr1a по сравнению с животными группы AAV-Tau[R406W], которым вводили физиологический раствор. Выявлено снижение экспрессии генов Bdnf и Ntrk2 в префронтальной коре после введения AAV-Tau[R406W]. При этом амисульприд в различных дозах (3 и 10 мг/кг) вызывал такое же снижение транскрипции этих генов у мышей без таупатии. Интересно также, что у мышей группы AAV-EGFP после введения амисульприда в дозе 10 мг/кг повышался уровень мРНК гена Ngfr. Полученные данные позволяют рассматривать амисульприд в качестве агента для восстановления нормальной функции тау-белка. Однако следует учитывать возможный негативный эффект амисульприда при длительном применении, отражающийся в увеличении экспрессии гена Ngfr и снижении экспрессии генов Bdnf и Ntrk2, что может указывать на усиление нейродегенеративных процессов.

Serotonin 5-HT7 receptors (5-HT7R) are attracting increasing attention as important participants in the mechanisms of Alzheimer’s disease and as a possible target for the treatment of various tau pathologies. In this study, we investigated the effects of amisulpride (5-HT7R inverse agonist) in C57BL/6J mice with experimentally induced expression of the gene encoding the aggregation-prone human Tau[R406W] protein in the prefrontal cortex. In these animals we examined short-term memory and the expression of genes involved in the development of tauopathy (Htr7 and Cdk5), as well as biomarkers of neurodegenerative processes – the Bdnf gene and its receptors TrkB (the Ntrk2 gene) and p75NTR (the Ngfr gene). In a short-term memory test, there was no difference in the discrimination index between mice treated with AAV-Tau[R406W] and mice treated with AAV-EGFP. Amisulpride did not affect this parameter. Administration of AAV-Tau[R406W] resulted in increased expression of the Htr7, Htr1a, and Cdk5 genes in the prefrontal cortex compared to AAV-EGFP animals. At the same time, amisulpride at the dose of 10 mg/kg in animals from the AAV-Tau[R406W] group caused a decrease in the Htr7, Htr1a genes mRNA levels compared to animals from the AAV-Tau[R406W] group treated with saline. A decrease in the expression of the Bdnf and Ntrk2 genes in the prefrontal cortex was revealed after administration of AAV-Tau[R406W]. Moreover, amisulpride at various doses (3 and 10 mg/kg) caused the same decrease in the transcription of these genes in mice without tauopathy. It is also interesting that in mice of the AAV-EGFP group, administration of amisulpride at the dose of 10 mg/kg increased the Ngfr gene mRNA level. The data obtained allow us to propose the use of amisulpride in restoring normal tau protein function. However, it should be noted that prolonged administration may result in adverse effects such as an increase in Ngfr expression and a decrease in Bdnf and Ntrk2 expression, which is probably indicative of an increase in neurodegenerative processes.

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