Amyloid β peptide decreases α7 receptor potentiation

Autores
Lasala, Matías Marcelo; Fabiani, Camila; Uranga, Romina Maria; Antollini, Silvia Susana; Corradi, Jeremias; Bouzat, Cecilia Beatriz
Año de publicación
2017
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Amyloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). Aβ is visible as the primary component of senile plaques in the brains of Alzheimer’s patients. Cholinergic activity mediated by human α7 nicotinic receptors is decreased in AD, and potentiation of α7 by positive allosteric modulators (PAMs) is emerging as a novel therapeutic strategy for improving memory and cognition. There are reports showing functional interaction of Aβ with α7, but the reported effects are very varied and the underlying mechanisms are not clear. Here we explored the effect of Aβ1-40 and Aβ1-42 on human α7 at the patch-clamp single-channel level. α7 channel activity elicited by 100 µM ACh consists of brief and iso lated openings. In the presence of PAMs, open channel lifetime is increased and openings appear grouped in long activation episodes. The type II PAM PNU-120596 (1 µM) prolongs open durations and elicits activation episodes of ~2 s. In the presence of Aβ there is a statistically significant decrease in the mean duration of the po tentiated activation episodes, which is 2.6-fold at 100 nM Aβ1-40 (p<0.001, n=11) and 2-fold at 100 nM Aβ1-42 (p<0.05, n=10). To determine if the effect is specific for PNU-120596, we also tested NS-1738, which is an α7 type I PAM. Again, a 2-fold reduction in the duration of the activation episodes is observed (p<0.001). Com plementary fluorescence spectroscopic studies using a fluorescent channel blocker, crystal violet, that binds with different affinities to resting and desensitized receptors provide insights into the function al changes. Our results demonstrate that Aβ inhibits potentiation of human α7, probably through an allosteric mechanism which involves slow block or increased desensitization. Deciphering the functional interaction between α7 and Aβ contributes to the understanding of the involvement of α7 in the pathophysiology of Alzheimer disease.
Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Reunión Conjunta de Sociedades de Biociencias
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Investigación Bioquímica y Biología Molecular
Sociedad Argentina de Inmunología
Sociedad Argentina de Andrologia
Sociedad Argentina de Biofísica
Sociedad Argentina de Farmacología Experimental
Sociedad Argentina de Fisiologia
Sociedad Argentina de Protozoologia
Materia
Amyloid β peptide
nicotinic receptor
Patch-clamp
ion channel
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/158478
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/158478
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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Amyloid β peptide decreases α7 receptor potentiationLasala, Matías MarceloFabiani, CamilaUranga, Romina MariaAntollini, Silvia SusanaCorradi, JeremiasBouzat, Cecilia BeatrizAmyloid β peptidenicotinic receptorPatch-clampion channelhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Amyloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). Aβ is visible as the primary component of senile plaques in the brains of Alzheimer’s patients. Cholinergic activity mediated by human α7 nicotinic receptors is decreased in AD, and potentiation of α7 by positive allosteric modulators (PAMs) is emerging as a novel therapeutic strategy for improving memory and cognition. There are reports showing functional interaction of Aβ with α7, but the reported effects are very varied and the underlying mechanisms are not clear. Here we explored the effect of Aβ1-40 and Aβ1-42 on human α7 at the patch-clamp single-channel level. α7 channel activity elicited by 100 µM ACh consists of brief and iso lated openings. In the presence of PAMs, open channel lifetime is increased and openings appear grouped in long activation episodes. The type II PAM PNU-120596 (1 µM) prolongs open durations and elicits activation episodes of ~2 s. In the presence of Aβ there is a statistically significant decrease in the mean duration of the po tentiated activation episodes, which is 2.6-fold at 100 nM Aβ1-40 (p<0.001, n=11) and 2-fold at 100 nM Aβ1-42 (p<0.05, n=10). To determine if the effect is specific for PNU-120596, we also tested NS-1738, which is an α7 type I PAM. Again, a 2-fold reduction in the duration of the activation episodes is observed (p<0.001). Com plementary fluorescence spectroscopic studies using a fluorescent channel blocker, crystal violet, that binds with different affinities to resting and desensitized receptors provide insights into the function al changes. Our results demonstrate that Aβ inhibits potentiation of human α7, probably through an allosteric mechanism which involves slow block or increased desensitization. Deciphering the functional interaction between α7 and Aβ contributes to the understanding of the involvement of α7 in the pathophysiology of Alzheimer disease.Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Corradi, Jeremias. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaReunión Conjunta de Sociedades de BiocienciasBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de Investigación Bioquímica y Biología MolecularSociedad Argentina de InmunologíaSociedad Argentina de AndrologiaSociedad Argentina de BiofísicaSociedad Argentina de Farmacología ExperimentalSociedad Argentina de FisiologiaSociedad Argentina de ProtozoologiaFundación Revista Medicina2017info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/158478Amyloid β peptide decreases α7 receptor potentiation; Reunión Conjunta de Sociedades de Biociencias; Buenos Aires; Argentina; 2017; 193-1940025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:11:19Zoai:ri.conicet.gov.ar:11336/158478instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:11:19.614CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Amyloid β peptide decreases α7 receptor potentiation
title Amyloid β peptide decreases α7 receptor potentiation
spellingShingle Amyloid β peptide decreases α7 receptor potentiation
Lasala, Matías Marcelo
Amyloid β peptide
nicotinic receptor
Patch-clamp
ion channel
title_short Amyloid β peptide decreases α7 receptor potentiation
title_full Amyloid β peptide decreases α7 receptor potentiation
title_fullStr Amyloid β peptide decreases α7 receptor potentiation
title_full_unstemmed Amyloid β peptide decreases α7 receptor potentiation
title_sort Amyloid β peptide decreases α7 receptor potentiation
dc.creator.none.fl_str_mv Lasala, Matías Marcelo
Fabiani, Camila
Uranga, Romina Maria
Antollini, Silvia Susana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author Lasala, Matías Marcelo
author_facet Lasala, Matías Marcelo
Fabiani, Camila
Uranga, Romina Maria
Antollini, Silvia Susana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author_role author
author2 Fabiani, Camila
Uranga, Romina Maria
Antollini, Silvia Susana
Corradi, Jeremias
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Amyloid β peptide
nicotinic receptor
Patch-clamp
ion channel
topic Amyloid β peptide
nicotinic receptor
Patch-clamp
ion channel
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Amyloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). Aβ is visible as the primary component of senile plaques in the brains of Alzheimer’s patients. Cholinergic activity mediated by human α7 nicotinic receptors is decreased in AD, and potentiation of α7 by positive allosteric modulators (PAMs) is emerging as a novel therapeutic strategy for improving memory and cognition. There are reports showing functional interaction of Aβ with α7, but the reported effects are very varied and the underlying mechanisms are not clear. Here we explored the effect of Aβ1-40 and Aβ1-42 on human α7 at the patch-clamp single-channel level. α7 channel activity elicited by 100 µM ACh consists of brief and iso lated openings. In the presence of PAMs, open channel lifetime is increased and openings appear grouped in long activation episodes. The type II PAM PNU-120596 (1 µM) prolongs open durations and elicits activation episodes of ~2 s. In the presence of Aβ there is a statistically significant decrease in the mean duration of the po tentiated activation episodes, which is 2.6-fold at 100 nM Aβ1-40 (p<0.001, n=11) and 2-fold at 100 nM Aβ1-42 (p<0.05, n=10). To determine if the effect is specific for PNU-120596, we also tested NS-1738, which is an α7 type I PAM. Again, a 2-fold reduction in the duration of the activation episodes is observed (p<0.001). Com plementary fluorescence spectroscopic studies using a fluorescent channel blocker, crystal violet, that binds with different affinities to resting and desensitized receptors provide insights into the function al changes. Our results demonstrate that Aβ inhibits potentiation of human α7, probably through an allosteric mechanism which involves slow block or increased desensitization. Deciphering the functional interaction between α7 and Aβ contributes to the understanding of the involvement of α7 in the pathophysiology of Alzheimer disease.
Fil: Lasala, Matías Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Uranga, Romina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Fil: Corradi, Jeremias. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina
Reunión Conjunta de Sociedades de Biociencias
Buenos Aires
Argentina
Sociedad Argentina de Investigación Clínica
Sociedad Argentina de Investigación Bioquímica y Biología Molecular
Sociedad Argentina de Inmunología
Sociedad Argentina de Andrologia
Sociedad Argentina de Biofísica
Sociedad Argentina de Farmacología Experimental
Sociedad Argentina de Fisiologia
Sociedad Argentina de Protozoologia
description Amyloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). Aβ is visible as the primary component of senile plaques in the brains of Alzheimer’s patients. Cholinergic activity mediated by human α7 nicotinic receptors is decreased in AD, and potentiation of α7 by positive allosteric modulators (PAMs) is emerging as a novel therapeutic strategy for improving memory and cognition. There are reports showing functional interaction of Aβ with α7, but the reported effects are very varied and the underlying mechanisms are not clear. Here we explored the effect of Aβ1-40 and Aβ1-42 on human α7 at the patch-clamp single-channel level. α7 channel activity elicited by 100 µM ACh consists of brief and iso lated openings. In the presence of PAMs, open channel lifetime is increased and openings appear grouped in long activation episodes. The type II PAM PNU-120596 (1 µM) prolongs open durations and elicits activation episodes of ~2 s. In the presence of Aβ there is a statistically significant decrease in the mean duration of the po tentiated activation episodes, which is 2.6-fold at 100 nM Aβ1-40 (p<0.001, n=11) and 2-fold at 100 nM Aβ1-42 (p<0.05, n=10). To determine if the effect is specific for PNU-120596, we also tested NS-1738, which is an α7 type I PAM. Again, a 2-fold reduction in the duration of the activation episodes is observed (p<0.001). Com plementary fluorescence spectroscopic studies using a fluorescent channel blocker, crystal violet, that binds with different affinities to resting and desensitized receptors provide insights into the function al changes. Our results demonstrate that Aβ inhibits potentiation of human α7, probably through an allosteric mechanism which involves slow block or increased desensitization. Deciphering the functional interaction between α7 and Aβ contributes to the understanding of the involvement of α7 in the pathophysiology of Alzheimer disease.
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/158478
Amyloid β peptide decreases α7 receptor potentiation; Reunión Conjunta de Sociedades de Biociencias; Buenos Aires; Argentina; 2017; 193-194
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/158478
identifier_str_mv Amyloid β peptide decreases α7 receptor potentiation; Reunión Conjunta de Sociedades de Biociencias; Buenos Aires; Argentina; 2017; 193-194
0025-7680
1669-9106
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicina
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
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dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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