|
ИСТИНА |
Войти в систему Регистрация |
ИПМех РАН |
||
Isomerization of Asp7 in Beta-Amyloid Enhances Inhibition of the alpha 7 Nicotinic Receptor and Promotes Neurotoxicityстатья
Статья опубликована в высокорейтинговом журнале
Информация о цитировании статьи получена из
Web of Science
Статья опубликована в журнале из списка Web of Science и/или Scopus
Дата последнего поиска статьи во внешних источниках: 27 февраля 2020 г.
- Авторы: Barykin E.P., Garifulina A.I., Kruykova E.V., Spirova E.N., Anashkina A.A., Adzhubei A.A., Shelukhina I.V., Kasheverov I.E., Mitkevich V.A., Kozin S.A., Hollmann M., Tsetlin V.I., Makarov A.A.
- Журнал: Cells
- Том: 8
- Номер: 8
- Год издания: 2019
- Издательство: MDPI
- Местоположение издательства: Basel, Switzerland
- Первая страница: 771
- DOI: 10.3390/cells8080771
- Аннотация: Cholinergic dysfunction in Alzheimer's disease (AD) can be mediated by the neuronal alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). Beta-amyloid peptide (A beta) binds to the alpha 7nAChR, disrupting the receptor's function and causing neurotoxicity. In vivo not only A beta but also its modified forms can drive AD pathogenesis. One of these forms, iso-A beta (containing an isomerized Asp7 residue), shows an increased neurotoxicity in vitro and stimulates amyloidogenesis in vivo. We suggested that such effects of iso-A beta are alpha 7nAChR-dependent. Here, using calcium imaging and electrophysiology, we found that iso-A beta is a more potent inhibitor of the alpha 7nAChR-mediated calcium current than unmodified A beta. However, Asp7 isomerization eliminated the ability of A beta to decrease the alpha 7nAChR levels. These data indicate differences in the interaction of the peptides with the alpha 7nAChR, which we demonstrated using computer modeling. Neither A beta nor iso-A beta competed with I-125-alpha-bungarotoxin for binding to the orthosteric site of the receptor, suggesting the allosteric binging mode of the peptides. Further we found that increased neurotoxicity of iso-A beta was mediated by the alpha 7nAChR. Thus, the isomerization of Asp7 enhances the inhibitory effect of A beta on the functional activity of the alpha 7nAChR, which may be an important factor in the disruption of the cholinergic system in AD.
- Добавил в систему: Смирнова Инна Григорьевна