Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis

Autores
Motamed, Zahra; Novack, Gisela Vanina; Heutschi, Daniel; Gaiser, Carine; Garcia, Corina Ileana; Do Carmo, Sonia; Cuello, A. Claudio; Morelli, Laura; Suter Dick, Laura
Año de publicación
2026
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Zahra Motamed and Gisela Novack (fisrt co-Authors)Mitochondrial dysfunction is a well-established hallmark of Alzheimer’s disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.
Fil: Motamed, Zahra. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Heutschi, Daniel. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Gaiser, Carine. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Garcia, Corina Ileana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Do Carmo, Sonia. McGill University; Canadá
Fil: Cuello, A. Claudio. McGill University; Canadá
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Suter Dick, Laura. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Materia
Alzheimer
mitochondrial dysfunction
Amyloidosis
Mitophagy
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:11336/289987
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/289987
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosisMotamed, ZahraNovack, Gisela VaninaHeutschi, DanielGaiser, CarineGarcia, Corina IleanaDo Carmo, SoniaCuello, A. ClaudioMorelli, LauraSuter Dick, LauraAlzheimermitochondrial dysfunctionAmyloidosisMitophagyhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Zahra Motamed and Gisela Novack (fisrt co-Authors)Mitochondrial dysfunction is a well-established hallmark of Alzheimer’s disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.Fil: Motamed, Zahra. University of Applied Sciences and Arts Northwestern Switzerlan; SuizaFil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Heutschi, Daniel. University of Applied Sciences and Arts Northwestern Switzerlan; SuizaFil: Gaiser, Carine. University of Applied Sciences and Arts Northwestern Switzerlan; SuizaFil: Garcia, Corina Ileana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Do Carmo, Sonia. McGill University; CanadáFil: Cuello, A. Claudio. McGill University; CanadáFil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Suter Dick, Laura. University of Applied Sciences and Arts Northwestern Switzerlan; SuizaElsevier Science Inc.2026-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/289987Motamed, Zahra; Novack, Gisela Vanina; Heutschi, Daniel; Gaiser, Carine; Garcia, Corina Ileana; et al.; Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis; Elsevier Science Inc.; Neurobiology of Aging; 161; 5-2026; 47-630197-4580CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S0197458026000126info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neurobiolaging.2026.01.006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:54:50Zoai:ri.conicet.gov.ar:11336/289987instacron: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:34982026-08-25 14:54:50.991CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
title Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
spellingShingle Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
Motamed, Zahra
Alzheimer
mitochondrial dysfunction
Amyloidosis
Mitophagy
title_short Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
title_full Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
title_fullStr Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
title_full_unstemmed Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
title_sort Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis
dc.creator.none.fl_str_mv Motamed, Zahra
Novack, Gisela Vanina
Heutschi, Daniel
Gaiser, Carine
Garcia, Corina Ileana
Do Carmo, Sonia
Cuello, A. Claudio
Morelli, Laura
Suter Dick, Laura
author Motamed, Zahra
author_facet Motamed, Zahra
Novack, Gisela Vanina
Heutschi, Daniel
Gaiser, Carine
Garcia, Corina Ileana
Do Carmo, Sonia
Cuello, A. Claudio
Morelli, Laura
Suter Dick, Laura
author_role author
author2 Novack, Gisela Vanina
Heutschi, Daniel
Gaiser, Carine
Garcia, Corina Ileana
Do Carmo, Sonia
Cuello, A. Claudio
Morelli, Laura
Suter Dick, Laura
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer
mitochondrial dysfunction
Amyloidosis
Mitophagy
topic Alzheimer
mitochondrial dysfunction
Amyloidosis
Mitophagy
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Zahra Motamed and Gisela Novack (fisrt co-Authors)Mitochondrial dysfunction is a well-established hallmark of Alzheimer’s disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.
Fil: Motamed, Zahra. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Novack, Gisela Vanina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Heutschi, Daniel. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Gaiser, Carine. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
Fil: Garcia, Corina Ileana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Do Carmo, Sonia. McGill University; Canadá
Fil: Cuello, A. Claudio. McGill University; Canadá
Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina
Fil: Suter Dick, Laura. University of Applied Sciences and Arts Northwestern Switzerlan; Suiza
description Zahra Motamed and Gisela Novack (fisrt co-Authors)Mitochondrial dysfunction is a well-established hallmark of Alzheimer’s disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.
publishDate 2026
dc.date.none.fl_str_mv 2026-05
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/11336/289987
Motamed, Zahra; Novack, Gisela Vanina; Heutschi, Daniel; Gaiser, Carine; Garcia, Corina Ileana; et al.; Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis; Elsevier Science Inc.; Neurobiology of Aging; 161; 5-2026; 47-63
0197-4580
CONICET Digital
CONICET
url http://hdl.handle.net/11336/289987
identifier_str_mv Motamed, Zahra; Novack, Gisela Vanina; Heutschi, Daniel; Gaiser, Carine; Garcia, Corina Ileana; et al.; Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis; Elsevier Science Inc.; Neurobiology of Aging; 161; 5-2026; 47-63
0197-4580
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://linkinghub.elsevier.com/retrieve/pii/S0197458026000126
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neurobiolaging.2026.01.006
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 Elsevier Science Inc.
publisher.none.fl_str_mv Elsevier Science Inc.
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 13.24418

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