Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism

Autores
Munafó, Juan Pablo; Maniscalchi Velásquez, Athina del Valle; Salvador, Gabriela Alejandra; Peñalva, Daniel Alejandro; Antollini, Silvia Susana
Año de publicación
2025
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Specific interactions between amyloid-β (Aβ) peptides and membrane lipids are increasingly recognized as key contributors to Alzheimer’s disease (AD) pathogenesis. Cholesterol (Chol), a major component of neuronal membranes — whose levels decline with aging but in AD occurred an altered Chol metabolism and asymmetric distribution, particularly between neuronal and synaptosomal membranes – plays a central role in modulating membrane properties and Aβ–membrane interactions. While Chol has been proposed to facilitate both membrane disruption and local Aβ aggregation, its precise role in fibrillation remains controversial. To address this issue, we investigated Aβ 1–40 aggregation using model membrane systems composed of POPC, sphingomyelin (bSM or 24:1 SM), and increasing amounts of Chol. Both monomeric and oligomeric preparations of Aβ 1-40 were used. Across all systems, time-resolved spectroscopy, fluorescence microscopy, dot blot, and TEM analyses revealed that Chol is necessary—but not sufficient —for full Aβ 1–40 aggregation. While Chol-rich bilayers promoted initial peptide anchoring and oligomerization, the progression to fibrillar structures critically depended on the presence of liquid-disordered membrane phases. Moreover, Aβ-induced vesicle disruption, lipid recruitment, and bilayer perturbations demonstrate that lipids act as active modulators—not passive scaffolds—of fibrillogenesis. Our findings support a surface-mediated aggregation mechanism in which Chol-rich membranes serve as catalytic platforms, increasing local peptide concentration and reducing diffusional dimensionality. Complementary experiments with acetylcholinesterase showed additional modulatory pathways. These findings advance our mechanistic understanding of Aβ aggregation at biological interfaces and offer broader implications for interface-driven self-assembly processes in complex colloidal systems.
Fil: Munafó, Juan Pablo. 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: Maniscalchi Velásquez, Athina del Valle. 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: Salvador, Gabriela Alejandra. 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: Peñalva, Daniel Alejandro. 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
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
Materia
AMYLOID-β
ALZHEIMER'S DISEASE
MODEL MEMBRANE SYSTEMS
CHOLESTEROL
ACETYLCHOLINESTERASE
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:11336/279651
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/279651
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanismMunafó, Juan PabloManiscalchi Velásquez, Athina del ValleSalvador, Gabriela AlejandraPeñalva, Daniel AlejandroAntollini, Silvia SusanaAMYLOID-βALZHEIMER'S DISEASEMODEL MEMBRANE SYSTEMSCHOLESTEROLACETYLCHOLINESTERASEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Specific interactions between amyloid-β (Aβ) peptides and membrane lipids are increasingly recognized as key contributors to Alzheimer’s disease (AD) pathogenesis. Cholesterol (Chol), a major component of neuronal membranes — whose levels decline with aging but in AD occurred an altered Chol metabolism and asymmetric distribution, particularly between neuronal and synaptosomal membranes – plays a central role in modulating membrane properties and Aβ–membrane interactions. While Chol has been proposed to facilitate both membrane disruption and local Aβ aggregation, its precise role in fibrillation remains controversial. To address this issue, we investigated Aβ 1–40 aggregation using model membrane systems composed of POPC, sphingomyelin (bSM or 24:1 SM), and increasing amounts of Chol. Both monomeric and oligomeric preparations of Aβ 1-40 were used. Across all systems, time-resolved spectroscopy, fluorescence microscopy, dot blot, and TEM analyses revealed that Chol is necessary—but not sufficient —for full Aβ 1–40 aggregation. While Chol-rich bilayers promoted initial peptide anchoring and oligomerization, the progression to fibrillar structures critically depended on the presence of liquid-disordered membrane phases. Moreover, Aβ-induced vesicle disruption, lipid recruitment, and bilayer perturbations demonstrate that lipids act as active modulators—not passive scaffolds—of fibrillogenesis. Our findings support a surface-mediated aggregation mechanism in which Chol-rich membranes serve as catalytic platforms, increasing local peptide concentration and reducing diffusional dimensionality. Complementary experiments with acetylcholinesterase showed additional modulatory pathways. These findings advance our mechanistic understanding of Aβ aggregation at biological interfaces and offer broader implications for interface-driven self-assembly processes in complex colloidal systems.Fil: Munafó, Juan Pablo. 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: Maniscalchi Velásquez, Athina del Valle. 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: Salvador, Gabriela Alejandra. 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: Peñalva, Daniel Alejandro. 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; ArgentinaLIII Reunión Anual de la Sociedad Argentina de BiofísicaBuenos AiresArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaVázquez, Diego EduardoDi Lella, Santiago2025info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/279651Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 98-98978-987-48938-3-3CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/congreso-2025/#resumenesNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:26:49Zoai:ri.conicet.gov.ar:11336/279651instacron: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:34982026-02-26 10:26:49.976CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
title Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
spellingShingle Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
Munafó, Juan Pablo
AMYLOID-β
ALZHEIMER'S DISEASE
MODEL MEMBRANE SYSTEMS
CHOLESTEROL
ACETYLCHOLINESTERASE
title_short Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
title_full Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
title_fullStr Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
title_full_unstemmed Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
title_sort Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism
dc.creator.none.fl_str_mv Munafó, Juan Pablo
Maniscalchi Velásquez, Athina del Valle
Salvador, Gabriela Alejandra
Peñalva, Daniel Alejandro
Antollini, Silvia Susana
author Munafó, Juan Pablo
author_facet Munafó, Juan Pablo
Maniscalchi Velásquez, Athina del Valle
Salvador, Gabriela Alejandra
Peñalva, Daniel Alejandro
Antollini, Silvia Susana
author_role author
author2 Maniscalchi Velásquez, Athina del Valle
Salvador, Gabriela Alejandra
Peñalva, Daniel Alejandro
Antollini, Silvia Susana
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Vázquez, Diego Eduardo
Di Lella, Santiago
dc.subject.none.fl_str_mv AMYLOID-β
ALZHEIMER'S DISEASE
MODEL MEMBRANE SYSTEMS
CHOLESTEROL
ACETYLCHOLINESTERASE
topic AMYLOID-β
ALZHEIMER'S DISEASE
MODEL MEMBRANE SYSTEMS
CHOLESTEROL
ACETYLCHOLINESTERASE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Specific interactions between amyloid-β (Aβ) peptides and membrane lipids are increasingly recognized as key contributors to Alzheimer’s disease (AD) pathogenesis. Cholesterol (Chol), a major component of neuronal membranes — whose levels decline with aging but in AD occurred an altered Chol metabolism and asymmetric distribution, particularly between neuronal and synaptosomal membranes – plays a central role in modulating membrane properties and Aβ–membrane interactions. While Chol has been proposed to facilitate both membrane disruption and local Aβ aggregation, its precise role in fibrillation remains controversial. To address this issue, we investigated Aβ 1–40 aggregation using model membrane systems composed of POPC, sphingomyelin (bSM or 24:1 SM), and increasing amounts of Chol. Both monomeric and oligomeric preparations of Aβ 1-40 were used. Across all systems, time-resolved spectroscopy, fluorescence microscopy, dot blot, and TEM analyses revealed that Chol is necessary—but not sufficient —for full Aβ 1–40 aggregation. While Chol-rich bilayers promoted initial peptide anchoring and oligomerization, the progression to fibrillar structures critically depended on the presence of liquid-disordered membrane phases. Moreover, Aβ-induced vesicle disruption, lipid recruitment, and bilayer perturbations demonstrate that lipids act as active modulators—not passive scaffolds—of fibrillogenesis. Our findings support a surface-mediated aggregation mechanism in which Chol-rich membranes serve as catalytic platforms, increasing local peptide concentration and reducing diffusional dimensionality. Complementary experiments with acetylcholinesterase showed additional modulatory pathways. These findings advance our mechanistic understanding of Aβ aggregation at biological interfaces and offer broader implications for interface-driven self-assembly processes in complex colloidal systems.
Fil: Munafó, Juan Pablo. 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: Maniscalchi Velásquez, Athina del Valle. 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: Salvador, Gabriela Alejandra. 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: Peñalva, Daniel Alejandro. 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
LIII Reunión Anual de la Sociedad Argentina de Biofísica
Buenos Aires
Argentina
Sociedad Argentina de Biofísica
description Specific interactions between amyloid-β (Aβ) peptides and membrane lipids are increasingly recognized as key contributors to Alzheimer’s disease (AD) pathogenesis. Cholesterol (Chol), a major component of neuronal membranes — whose levels decline with aging but in AD occurred an altered Chol metabolism and asymmetric distribution, particularly between neuronal and synaptosomal membranes – plays a central role in modulating membrane properties and Aβ–membrane interactions. While Chol has been proposed to facilitate both membrane disruption and local Aβ aggregation, its precise role in fibrillation remains controversial. To address this issue, we investigated Aβ 1–40 aggregation using model membrane systems composed of POPC, sphingomyelin (bSM or 24:1 SM), and increasing amounts of Chol. Both monomeric and oligomeric preparations of Aβ 1-40 were used. Across all systems, time-resolved spectroscopy, fluorescence microscopy, dot blot, and TEM analyses revealed that Chol is necessary—but not sufficient —for full Aβ 1–40 aggregation. While Chol-rich bilayers promoted initial peptide anchoring and oligomerization, the progression to fibrillar structures critically depended on the presence of liquid-disordered membrane phases. Moreover, Aβ-induced vesicle disruption, lipid recruitment, and bilayer perturbations demonstrate that lipids act as active modulators—not passive scaffolds—of fibrillogenesis. Our findings support a surface-mediated aggregation mechanism in which Chol-rich membranes serve as catalytic platforms, increasing local peptide concentration and reducing diffusional dimensionality. Complementary experiments with acetylcholinesterase showed additional modulatory pathways. These findings advance our mechanistic understanding of Aβ aggregation at biological interfaces and offer broader implications for interface-driven self-assembly processes in complex colloidal systems.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
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/11336/279651
Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 98-98
978-987-48938-3-3
CONICET Digital
CONICET
url http://hdl.handle.net/11336/279651
identifier_str_mv Lipid-dependent two-step interfacially-driven Aβ 1–40 aggregation mechanism; LIII Reunión Anual de la Sociedad Argentina de Biofísica; Buenos Aires; Argentina; 2025; 98-98
978-987-48938-3-3
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://biofisica.org.ar/congreso-2025/#resumenes
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 Nacional
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 13.176822

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