Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling

Autores
Antonino, Magdalena; Marmo, Paula; Freites, Carlos Leandro; Quassollo Infanzon, Gonzalo Emiliano; Sánchez, Maria Florencia; Lorenzo, Alfredo Guillermo; Bignante, Elena Anahi
Año de publicación
2022
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Alzheimer’s disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. Aβ is generated by the successive cleavage of the amyloid precursor protein (APP), first by β-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aβ aggregation and the development of AD. In vitro studies have demonstrated that Aβ assemblies spark a feed-forward loop heightening Aβ production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aβ enhance colocalization and physical interaction of APP and BACE1 in recycling endosomes of human neurons derived from induced pluripotent stem cells and other cell types, which leads to exacerbated amyloidogenic processing of APP and intracellular accumulation of Aβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβ or to activate Go protein, we have found that treatment with aggregated Aβ fails to increase colocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in this process. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, and intracellular accumulation of Aβ42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aβ pathology in the early stages of AD and suggest that gallein could have therapeutic potential.
Fil: Antonino, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Marmo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Quassollo Infanzon, Gonzalo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba,; Argentina
Fil: Sánchez, Maria Florencia. Goethe Universitat Frankfurt; Alemania
Fil: Lorenzo, Alfredo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Bignante, Elena Anahi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina
Materia
ALZHEIMER’S DISEASE
AMYLOID BETA
AMYLOID PRECURSOR PROTEIN
BACE1
GALLEIN
GΒΓ SUBUNIT
HUMAN NEURONS
IPSC
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/204699
Acceder
id CONICETDig_4a7bb373007a0e3edfd21bda9cf47858
oai_identifier_str oai:ri.conicet.gov.ar:11336/204699
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ SignalingAntonino, MagdalenaMarmo, PaulaFreites, Carlos LeandroQuassollo Infanzon, Gonzalo EmilianoSánchez, Maria FlorenciaLorenzo, Alfredo GuillermoBignante, Elena AnahiALZHEIMER’S DISEASEAMYLOID BETAAMYLOID PRECURSOR PROTEINBACE1GALLEINGΒΓ SUBUNITHUMAN NEURONSIPSChttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Alzheimer’s disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. Aβ is generated by the successive cleavage of the amyloid precursor protein (APP), first by β-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aβ aggregation and the development of AD. In vitro studies have demonstrated that Aβ assemblies spark a feed-forward loop heightening Aβ production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aβ enhance colocalization and physical interaction of APP and BACE1 in recycling endosomes of human neurons derived from induced pluripotent stem cells and other cell types, which leads to exacerbated amyloidogenic processing of APP and intracellular accumulation of Aβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβ or to activate Go protein, we have found that treatment with aggregated Aβ fails to increase colocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in this process. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, and intracellular accumulation of Aβ42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aβ pathology in the early stages of AD and suggest that gallein could have therapeutic potential.Fil: Antonino, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Marmo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Quassollo Infanzon, Gonzalo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba,; ArgentinaFil: Sánchez, Maria Florencia. Goethe Universitat Frankfurt; AlemaniaFil: Lorenzo, Alfredo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Bignante, Elena Anahi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; ArgentinaFrontiers Media2022-04-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/204699Antonino, Magdalena; Marmo, Paula; Freites, Carlos Leandro; Quassollo Infanzon, Gonzalo Emiliano; Sánchez, Maria Florencia; et al.; Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling; Frontiers Media; Frontiers in Cell and Developmental Biology; 10; 4-4-2022; 1-162296-634XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2022.852738/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2022.852738info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:03:48Zoai:ri.conicet.gov.ar:11336/204699instacron: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:34982025-09-29 10:03:48.477CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
title Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
spellingShingle Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
Antonino, Magdalena
ALZHEIMER’S DISEASE
AMYLOID BETA
AMYLOID PRECURSOR PROTEIN
BACE1
GALLEIN
GΒΓ SUBUNIT
HUMAN NEURONS
IPSC
title_short Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
title_full Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
title_fullStr Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
title_full_unstemmed Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
title_sort Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
dc.creator.none.fl_str_mv Antonino, Magdalena
Marmo, Paula
Freites, Carlos Leandro
Quassollo Infanzon, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo Guillermo
Bignante, Elena Anahi
author Antonino, Magdalena
author_facet Antonino, Magdalena
Marmo, Paula
Freites, Carlos Leandro
Quassollo Infanzon, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo Guillermo
Bignante, Elena Anahi
author_role author
author2 Marmo, Paula
Freites, Carlos Leandro
Quassollo Infanzon, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo Guillermo
Bignante, Elena Anahi
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ALZHEIMER’S DISEASE
AMYLOID BETA
AMYLOID PRECURSOR PROTEIN
BACE1
GALLEIN
GΒΓ SUBUNIT
HUMAN NEURONS
IPSC
topic ALZHEIMER’S DISEASE
AMYLOID BETA
AMYLOID PRECURSOR PROTEIN
BACE1
GALLEIN
GΒΓ SUBUNIT
HUMAN NEURONS
IPSC
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Alzheimer’s disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. Aβ is generated by the successive cleavage of the amyloid precursor protein (APP), first by β-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aβ aggregation and the development of AD. In vitro studies have demonstrated that Aβ assemblies spark a feed-forward loop heightening Aβ production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aβ enhance colocalization and physical interaction of APP and BACE1 in recycling endosomes of human neurons derived from induced pluripotent stem cells and other cell types, which leads to exacerbated amyloidogenic processing of APP and intracellular accumulation of Aβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβ or to activate Go protein, we have found that treatment with aggregated Aβ fails to increase colocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in this process. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, and intracellular accumulation of Aβ42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aβ pathology in the early stages of AD and suggest that gallein could have therapeutic potential.
Fil: Antonino, Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Marmo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Freites, Carlos Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Quassollo Infanzon, Gonzalo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba,; Argentina
Fil: Sánchez, Maria Florencia. Goethe Universitat Frankfurt; Alemania
Fil: Lorenzo, Alfredo Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina
Fil: Bignante, Elena Anahi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina
description Alzheimer’s disease (AD) is characterized by the deposition of aggregated species of amyloid beta (Aβ) in the brain, which leads to progressive cognitive deficits and dementia. Aβ is generated by the successive cleavage of the amyloid precursor protein (APP), first by β-site APP cleaving enzyme 1 (BACE1) and subsequently by the γ-secretase complex. Those conditions which enhace or reduce its clearance predispose to Aβ aggregation and the development of AD. In vitro studies have demonstrated that Aβ assemblies spark a feed-forward loop heightening Aβ production. However, the underlying mechanism remains unknown. Here, we show that oligomers and fibrils of Aβ enhance colocalization and physical interaction of APP and BACE1 in recycling endosomes of human neurons derived from induced pluripotent stem cells and other cell types, which leads to exacerbated amyloidogenic processing of APP and intracellular accumulation of Aβ42. In cells that are overexpressing the mutant forms of APP which are unable to bind Aβ or to activate Go protein, we have found that treatment with aggregated Aβ fails to increase colocalization of APP with BACE1 indicating that Aβ-APP/Go signaling is involved in this process. Moreover, inhibition of Gβγ subunit signaling with βARKct or gallein prevents Aβ-dependent interaction of APP and BACE1 in endosomes, β-processing of APP, and intracellular accumulation of Aβ42. Collectively, our findings uncover a signaling mechanism leading to a feed-forward loop of amyloidogenesis that might contribute to Aβ pathology in the early stages of AD and suggest that gallein could have therapeutic potential.
publishDate 2022
dc.date.none.fl_str_mv 2022-04-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/204699
Antonino, Magdalena; Marmo, Paula; Freites, Carlos Leandro; Quassollo Infanzon, Gonzalo Emiliano; Sánchez, Maria Florencia; et al.; Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling; Frontiers Media; Frontiers in Cell and Developmental Biology; 10; 4-4-2022; 1-16
2296-634X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/204699
identifier_str_mv Antonino, Magdalena; Marmo, Paula; Freites, Carlos Leandro; Quassollo Infanzon, Gonzalo Emiliano; Sánchez, Maria Florencia; et al.; Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling; Frontiers Media; Frontiers in Cell and Developmental Biology; 10; 4-4-2022; 1-16
2296-634X
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.frontiersin.org/articles/10.3389/fcell.2022.852738/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fcell.2022.852738
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
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
_version_ 1844613858458599424
score 13.070432

Publicaciones similares