Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides

Autores
Lasala, Matías Marcelo; Fabiani, Camila; Corradi, Jeremias; Antollini, Silvia Susana; Bouzat, Cecilia Beatriz
Año de publicación
2018
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
myloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1-40 and Aβ1-42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV), which shows different affinities for resting and desensitized states, revealed that Aβ induces α7 concentration-dependent conformational changes. At 100 pM, Aβ displaces CrV Kd value for the resting state towards that of the desensitized state from which α7 is still reactive to carbamycholine (Carb). These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, indicating the stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the durations of the activation episodes elicited by ACh are significantly reduced, an effect compatible with slow open- channel block. We conclude that Aβ directly affects α7 function and acts as an agonist and a negative modulator: activation of α7 by low Aβ concentrations may be involved in beneficial physiological effects, and the reduced α7 activity in the presence of higher Aβ concentrations may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD
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
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
Fil: Corradi, Jeremias. 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: 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
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
XLVII Reunión Anual de la Sociedad Argentina de Biofísica
La Plata
Argentina
Sociedad Argentina de Biofísica
Materia
NICOTINIC RECEPTORS
MODULATION
NEURODEGENERATION
AMYLOID BETA
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:11336/231803
Acceder
id CONICETDig_09220e9eed7f13827ba50762391d0254
oai_identifier_str oai:ri.conicet.gov.ar:11336/231803
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptidesLasala, Matías MarceloFabiani, CamilaCorradi, JeremiasAntollini, Silvia SusanaBouzat, Cecilia BeatrizNICOTINIC RECEPTORSMODULATIONNEURODEGENERATIONAMYLOID BETAhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1myloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1-40 and Aβ1-42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV), which shows different affinities for resting and desensitized states, revealed that Aβ induces α7 concentration-dependent conformational changes. At 100 pM, Aβ displaces CrV Kd value for the resting state towards that of the desensitized state from which α7 is still reactive to carbamycholine (Carb). These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, indicating the stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the durations of the activation episodes elicited by ACh are significantly reduced, an effect compatible with slow open- channel block. We conclude that Aβ directly affects α7 function and acts as an agonist and a negative modulator: activation of α7 by low Aβ concentrations may be involved in beneficial physiological effects, and the reduced α7 activity in the presence of higher Aβ concentrations may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of ADFil: 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; 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; ArgentinaFil: Corradi, Jeremias. 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: 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; 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; ArgentinaXLVII Reunión Anual de la Sociedad Argentina de BiofísicaLa PlataArgentinaSociedad Argentina de BiofísicaSociedad Argentina de Biofísica2018info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/231803Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides; XLVII Reunión Anual de la Sociedad Argentina de Biofísica; La Plata; Argentina; 2018; 104-104978-987-27591-6-2CONICET DigitalCONICETengInternacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:57:17Zoai:ri.conicet.gov.ar:11336/231803instacron: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 09:57:18.222CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
title Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
spellingShingle Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
Lasala, Matías Marcelo
NICOTINIC RECEPTORS
MODULATION
NEURODEGENERATION
AMYLOID BETA
title_short Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
title_full Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
title_fullStr Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
title_full_unstemmed Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
title_sort Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides
dc.creator.none.fl_str_mv Lasala, Matías Marcelo
Fabiani, Camila
Corradi, Jeremias
Antollini, Silvia Susana
Bouzat, Cecilia Beatriz
author Lasala, Matías Marcelo
author_facet Lasala, Matías Marcelo
Fabiani, Camila
Corradi, Jeremias
Antollini, Silvia Susana
Bouzat, Cecilia Beatriz
author_role author
author2 Fabiani, Camila
Corradi, Jeremias
Antollini, Silvia Susana
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv NICOTINIC RECEPTORS
MODULATION
NEURODEGENERATION
AMYLOID BETA
topic NICOTINIC RECEPTORS
MODULATION
NEURODEGENERATION
AMYLOID BETA
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv myloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1-40 and Aβ1-42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV), which shows different affinities for resting and desensitized states, revealed that Aβ induces α7 concentration-dependent conformational changes. At 100 pM, Aβ displaces CrV Kd value for the resting state towards that of the desensitized state from which α7 is still reactive to carbamycholine (Carb). These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, indicating the stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the durations of the activation episodes elicited by ACh are significantly reduced, an effect compatible with slow open- channel block. We conclude that Aβ directly affects α7 function and acts as an agonist and a negative modulator: activation of α7 by low Aβ concentrations may be involved in beneficial physiological effects, and the reduced α7 activity in the presence of higher Aβ concentrations may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD
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
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
Fil: Corradi, Jeremias. 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: 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
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
XLVII Reunión Anual de la Sociedad Argentina de Biofísica
La Plata
Argentina
Sociedad Argentina de Biofísica
description myloid β peptide (Aβ) is a key player in the development of Alzheimer disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1-40 and Aβ1-42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV), which shows different affinities for resting and desensitized states, revealed that Aβ induces α7 concentration-dependent conformational changes. At 100 pM, Aβ displaces CrV Kd value for the resting state towards that of the desensitized state from which α7 is still reactive to carbamycholine (Carb). These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, indicating the stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the durations of the activation episodes elicited by ACh are significantly reduced, an effect compatible with slow open- channel block. We conclude that Aβ directly affects α7 function and acts as an agonist and a negative modulator: activation of α7 by low Aβ concentrations may be involved in beneficial physiological effects, and the reduced α7 activity in the presence of higher Aβ concentrations may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Book
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/11336/231803
Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides; XLVII Reunión Anual de la Sociedad Argentina de Biofísica; La Plata; Argentina; 2018; 104-104
978-987-27591-6-2
CONICET Digital
CONICET
url http://hdl.handle.net/11336/231803
identifier_str_mv Molecular modulation of human α7 Nicotinic Receptor by amyloid-β peptides; XLVII Reunión Anual de la Sociedad Argentina de Biofísica; La Plata; Argentina; 2018; 104-104
978-987-27591-6-2
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Sociedad Argentina de Biofísica
publisher.none.fl_str_mv Sociedad Argentina de Biofísica
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
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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score 13.13397

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