Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease

Autores
Martino Adami, Pamela Victoria; Nichtová, Zuzana; Weaver, David B.; Bartok, Adam; Wisniewski, Thomas; Jones, Drew R.; Do Carmo, Sonia; Castaño, Eduardo Miguel; Cuello, Claudio A.; Hajnóczky, György; Morelli, Laura
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca2+-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid- MERCs:totalMERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons. This article has an associated First Person interview with the first author of the paper.
Fil: Martino Adami, Pamela Victoria. 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. Universitat zu Köln; Alemania
Fil: Nichtová, Zuzana. Thomas Jefferson University; Estados Unidos
Fil: Weaver, David B.. Thomas Jefferson University; Estados Unidos
Fil: Bartok, Adam. Thomas Jefferson University; Estados Unidos
Fil: Wisniewski, Thomas. University of New York; Estados Unidos
Fil: Jones, Drew R.. University of New York; Estados Unidos
Fil: Do Carmo, Sonia. Mcgill University; Canadá
Fil: Castaño, Eduardo Miguel. 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: Cuello, Claudio A.. Mcgill University; Canadá
Fil: Hajnóczky, György. Thomas Jefferson University; Estados Unidos
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
Materia
ALZHEIMER
AMYLOID β/βCTF
FRET
MERC
MITOCHONDRIAL LIPIDS
PRIMARY NEURONAL CULTURES
TRANSGENIC RATS
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:11336/96782

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repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's diseaseMartino Adami, Pamela VictoriaNichtová, ZuzanaWeaver, David B.Bartok, AdamWisniewski, ThomasJones, Drew R.Do Carmo, SoniaCastaño, Eduardo MiguelCuello, Claudio A.Hajnóczky, GyörgyMorelli, LauraALZHEIMERAMYLOID β/βCTFFRETMERCMITOCHONDRIAL LIPIDSPRIMARY NEURONAL CULTURESTRANSGENIC RATShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca2+-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid- MERCs:totalMERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons. This article has an associated First Person interview with the first author of the paper.Fil: Martino Adami, Pamela Victoria. 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. Universitat zu Köln; AlemaniaFil: Nichtová, Zuzana. Thomas Jefferson University; Estados UnidosFil: Weaver, David B.. Thomas Jefferson University; Estados UnidosFil: Bartok, Adam. Thomas Jefferson University; Estados UnidosFil: Wisniewski, Thomas. University of New York; Estados UnidosFil: Jones, Drew R.. University of New York; Estados UnidosFil: Do Carmo, Sonia. Mcgill University; CanadáFil: Castaño, Eduardo Miguel. 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: Cuello, Claudio A.. Mcgill University; CanadáFil: Hajnóczky, György. Thomas Jefferson University; Estados UnidosFil: 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; ArgentinaCompany of Biologists2019-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/96782Martino Adami, Pamela Victoria; Nichtová, Zuzana; Weaver, David B.; Bartok, Adam; Wisniewski, Thomas; et al.; Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease; Company of Biologists; Journal of Cell Science; 132; 20; 10-20190021-9533CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1242/jcs.229906info:eu-repo/semantics/altIdentifier/url/https://jcs.biologists.org/content/132/20/jcs229906info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:14:13Zoai:ri.conicet.gov.ar:11336/96782instacron: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 10:14:13.762CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
title Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
spellingShingle Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
Martino Adami, Pamela Victoria
ALZHEIMER
AMYLOID β/βCTF
FRET
MERC
MITOCHONDRIAL LIPIDS
PRIMARY NEURONAL CULTURES
TRANSGENIC RATS
title_short Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
title_full Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
title_fullStr Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
title_full_unstemmed Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
title_sort Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease
dc.creator.none.fl_str_mv Martino Adami, Pamela Victoria
Nichtová, Zuzana
Weaver, David B.
Bartok, Adam
Wisniewski, Thomas
Jones, Drew R.
Do Carmo, Sonia
Castaño, Eduardo Miguel
Cuello, Claudio A.
Hajnóczky, György
Morelli, Laura
author Martino Adami, Pamela Victoria
author_facet Martino Adami, Pamela Victoria
Nichtová, Zuzana
Weaver, David B.
Bartok, Adam
Wisniewski, Thomas
Jones, Drew R.
Do Carmo, Sonia
Castaño, Eduardo Miguel
Cuello, Claudio A.
Hajnóczky, György
Morelli, Laura
author_role author
author2 Nichtová, Zuzana
Weaver, David B.
Bartok, Adam
Wisniewski, Thomas
Jones, Drew R.
Do Carmo, Sonia
Castaño, Eduardo Miguel
Cuello, Claudio A.
Hajnóczky, György
Morelli, Laura
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ALZHEIMER
AMYLOID β/βCTF
FRET
MERC
MITOCHONDRIAL LIPIDS
PRIMARY NEURONAL CULTURES
TRANSGENIC RATS
topic ALZHEIMER
AMYLOID β/βCTF
FRET
MERC
MITOCHONDRIAL LIPIDS
PRIMARY NEURONAL CULTURES
TRANSGENIC RATS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca2+-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid- MERCs:totalMERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons. This article has an associated First Person interview with the first author of the paper.
Fil: Martino Adami, Pamela Victoria. 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. Universitat zu Köln; Alemania
Fil: Nichtová, Zuzana. Thomas Jefferson University; Estados Unidos
Fil: Weaver, David B.. Thomas Jefferson University; Estados Unidos
Fil: Bartok, Adam. Thomas Jefferson University; Estados Unidos
Fil: Wisniewski, Thomas. University of New York; Estados Unidos
Fil: Jones, Drew R.. University of New York; Estados Unidos
Fil: Do Carmo, Sonia. Mcgill University; Canadá
Fil: Castaño, Eduardo Miguel. 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: Cuello, Claudio A.. Mcgill University; Canadá
Fil: Hajnóczky, György. Thomas Jefferson University; Estados Unidos
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
description The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca2+-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid- MERCs:totalMERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons. This article has an associated First Person interview with the first author of the paper.
publishDate 2019
dc.date.none.fl_str_mv 2019-10
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/11336/96782
Martino Adami, Pamela Victoria; Nichtová, Zuzana; Weaver, David B.; Bartok, Adam; Wisniewski, Thomas; et al.; Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease; Company of Biologists; Journal of Cell Science; 132; 20; 10-2019
0021-9533
CONICET Digital
CONICET
url http://hdl.handle.net/11336/96782
identifier_str_mv Martino Adami, Pamela Victoria; Nichtová, Zuzana; Weaver, David B.; Bartok, Adam; Wisniewski, Thomas; et al.; Perturbed mitochondria-ER contacts in live neurons that model the amyloid pathology of Alzheimer's disease; Company of Biologists; Journal of Cell Science; 132; 20; 10-2019
0021-9533
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1242/jcs.229906
info:eu-repo/semantics/altIdentifier/url/https://jcs.biologists.org/content/132/20/jcs229906
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
dc.publisher.none.fl_str_mv Company of Biologists
publisher.none.fl_str_mv Company of Biologists
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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