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dc.contributor.author
Antonino, Magdalena
dc.contributor.author
Marmo, Paula
dc.contributor.author
Freites, Carlos Leandro
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Quassollo Infanzon, Gonzalo Emiliano
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Sánchez, Maria Florencia
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Lorenzo, Alfredo Guillermo
dc.contributor.author
Bignante, Elena Anahi
dc.date.available
2023-07-20T18:34:33Z
dc.date.issued
2022-04-04
dc.identifier.citation
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
dc.identifier.uri
http://hdl.handle.net/11336/204699
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Frontiers Media
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
ALZHEIMER’S DISEASE
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AMYLOID BETA
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AMYLOID PRECURSOR PROTEIN
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BACE1
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GALLEIN
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GΒΓ SUBUNIT
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HUMAN NEURONS
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IPSC
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Otros Tópicos Biológicos
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2023-07-18T14:26:13Z
dc.identifier.eissn
2296-634X
dc.journal.volume
10
dc.journal.pagination
1-16
dc.journal.pais
Suiza
dc.description.fil
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
dc.description.fil
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
dc.description.fil
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
dc.description.fil
Fil: Quassollo Infanzon, Gonzalo Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Universidad Nacional de Córdoba,; Argentina
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Fil: Sánchez, Maria Florencia. Goethe Universitat Frankfurt; Alemania
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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
dc.description.fil
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
dc.journal.title
Frontiers in Cell and Developmental Biology
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fcell.2022.852738/full
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.3389/fcell.2022.852738
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