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

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 (B...

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Autores principales: Antonino, Magdalena, Marmo, Paula, Freites, Carlos Leandro, Quassollo, Gonzalo Emiliano, Sánchez, Maria Florencia, Lorenzo, Alfredo, Bignante, Elena Anahi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013780/
https://www.ncbi.nlm.nih.gov/pubmed/35445022
http://dx.doi.org/10.3389/fcell.2022.852738
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author Antonino, Magdalena
Marmo, Paula
Freites, Carlos Leandro
Quassollo, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo
Bignante, Elena Anahi
author_facet Antonino, Magdalena
Marmo, Paula
Freites, Carlos Leandro
Quassollo, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo
Bignante, Elena Anahi
author_sort Antonino, Magdalena
collection PubMed
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.
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spelling pubmed-90137802022-04-19 Aβ Assemblies Promote Amyloidogenic Processing of APP and Intracellular Accumulation of Aβ42 Through Go/Gβγ Signaling Antonino, Magdalena Marmo, Paula Freites, Carlos Leandro Quassollo, Gonzalo Emiliano Sánchez, Maria Florencia Lorenzo, Alfredo Bignante, Elena Anahi Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2022-04-04 /pmc/articles/PMC9013780/ /pubmed/35445022 http://dx.doi.org/10.3389/fcell.2022.852738 Text en Copyright © 2022 Antonino, Marmo, Freites, Quassollo, Sánchez, Lorenzo and Bignante. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Antonino, Magdalena
Marmo, Paula
Freites, Carlos Leandro
Quassollo, Gonzalo Emiliano
Sánchez, Maria Florencia
Lorenzo, Alfredo
Bignante, Elena Anahi
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
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_short 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
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9013780/
https://www.ncbi.nlm.nih.gov/pubmed/35445022
http://dx.doi.org/10.3389/fcell.2022.852738
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