Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ

The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent finding...

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Autores principales: Barykin, Evgeny P., Garifulina, Aleksandra I., Tolstova, Anna P., Anashkina, Anastasia A., Adzhubei, Alexei A., Mezentsev, Yuri V., Shelukhina, Irina V., Kozin, Sergey A., Tsetlin, Victor I., Makarov, Alexander A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504039/
https://www.ncbi.nlm.nih.gov/pubmed/32872553
http://dx.doi.org/10.3390/ijms21176272
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author Barykin, Evgeny P.
Garifulina, Aleksandra I.
Tolstova, Anna P.
Anashkina, Anastasia A.
Adzhubei, Alexei A.
Mezentsev, Yuri V.
Shelukhina, Irina V.
Kozin, Sergey A.
Tsetlin, Victor I.
Makarov, Alexander A.
author_facet Barykin, Evgeny P.
Garifulina, Aleksandra I.
Tolstova, Anna P.
Anashkina, Anastasia A.
Adzhubei, Alexei A.
Mezentsev, Yuri V.
Shelukhina, Irina V.
Kozin, Sergey A.
Tsetlin, Victor I.
Makarov, Alexander A.
author_sort Barykin, Evgeny P.
collection PubMed
description The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the (11)EVHH(14) site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of (11)EVHH(14) with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a (35)HAEE(38) site in α4β2 nAChR, which is charge-complementary to (11)EVHH(14), and molecular modeling showed that a stable Aβ(42)-α4β2 nAChR complex could be formed via the (11)EVHH(14):(35)HAEE(38) interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH(2) can bind to Aβ via (11)EVHH(14) site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH(2) tetrapeptide completely abolishes the Aβ(42)-induced inhibition of α4β2 nAChR. Thus, we suggest that (35)HAEE(38) is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH(2) tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD.
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spelling pubmed-75040392020-09-24 Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ Barykin, Evgeny P. Garifulina, Aleksandra I. Tolstova, Anna P. Anashkina, Anastasia A. Adzhubei, Alexei A. Mezentsev, Yuri V. Shelukhina, Irina V. Kozin, Sergey A. Tsetlin, Victor I. Makarov, Alexander A. Int J Mol Sci Article The cholinergic deficit in Alzheimer’s disease (AD) may arise from selective loss of cholinergic neurons caused by the binding of Aβ peptide to nicotinic acetylcholine receptors (nAChRs). Thus, compounds preventing such an interaction are needed to address the cholinergic dysfunction. Recent findings suggest that the (11)EVHH(14) site in Aβ peptide mediates its interaction with α4β2 nAChR. This site contains several charged amino acid residues, hence we hypothesized that the formation of Aβ-α4β2 nAChR complex is based on the interaction of (11)EVHH(14) with its charge-complementary counterpart in α4β2 nAChR. Indeed, we discovered a (35)HAEE(38) site in α4β2 nAChR, which is charge-complementary to (11)EVHH(14), and molecular modeling showed that a stable Aβ(42)-α4β2 nAChR complex could be formed via the (11)EVHH(14):(35)HAEE(38) interface. Using surface plasmon resonance and bioinformatics approaches, we further showed that a corresponding tetrapeptide Ac-HAEE-NH(2) can bind to Aβ via (11)EVHH(14) site. Finally, using two-electrode voltage clamp in Xenopus laevis oocytes, we showed that Ac-HAEE-NH(2) tetrapeptide completely abolishes the Aβ(42)-induced inhibition of α4β2 nAChR. Thus, we suggest that (35)HAEE(38) is a potential binding site for Aβ on α4β2 nAChR and Ac-HAEE-NH(2) tetrapeptide corresponding to this site is a potential therapeutic for the treatment of α4β2 nAChR-dependent cholinergic dysfunction in AD. MDPI 2020-08-29 /pmc/articles/PMC7504039/ /pubmed/32872553 http://dx.doi.org/10.3390/ijms21176272 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Barykin, Evgeny P.
Garifulina, Aleksandra I.
Tolstova, Anna P.
Anashkina, Anastasia A.
Adzhubei, Alexei A.
Mezentsev, Yuri V.
Shelukhina, Irina V.
Kozin, Sergey A.
Tsetlin, Victor I.
Makarov, Alexander A.
Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title_full Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title_fullStr Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title_full_unstemmed Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title_short Tetrapeptide Ac-HAEE-NH(2) Protects α4β2 nAChR from Inhibition by Aβ
title_sort tetrapeptide ac-haee-nh(2) protects α4β2 nachr from inhibition by aβ
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504039/
https://www.ncbi.nlm.nih.gov/pubmed/32872553
http://dx.doi.org/10.3390/ijms21176272
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