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Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models

Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as...

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Autores principales: Leal, Nuno Santos, Dentoni, Giacomo, Schreiner, Bernadette, Naia, Luana, Piras, Antonio, Graff, Caroline, Cattaneo, Antonio, Meli, Giovanni, Hamasaki, Maho, Nilsson, Per, Ankarcrona, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760163/
https://www.ncbi.nlm.nih.gov/pubmed/33260715
http://dx.doi.org/10.3390/cells9122552
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author Leal, Nuno Santos
Dentoni, Giacomo
Schreiner, Bernadette
Naia, Luana
Piras, Antonio
Graff, Caroline
Cattaneo, Antonio
Meli, Giovanni
Hamasaki, Maho
Nilsson, Per
Ankarcrona, Maria
author_facet Leal, Nuno Santos
Dentoni, Giacomo
Schreiner, Bernadette
Naia, Luana
Piras, Antonio
Graff, Caroline
Cattaneo, Antonio
Meli, Giovanni
Hamasaki, Maho
Nilsson, Per
Ankarcrona, Maria
author_sort Leal, Nuno Santos
collection PubMed
description Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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spelling pubmed-77601632020-12-26 Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models Leal, Nuno Santos Dentoni, Giacomo Schreiner, Bernadette Naia, Luana Piras, Antonio Graff, Caroline Cattaneo, Antonio Meli, Giovanni Hamasaki, Maho Nilsson, Per Ankarcrona, Maria Cells Article Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD. MDPI 2020-11-28 /pmc/articles/PMC7760163/ /pubmed/33260715 http://dx.doi.org/10.3390/cells9122552 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Leal, Nuno Santos
Dentoni, Giacomo
Schreiner, Bernadette
Naia, Luana
Piras, Antonio
Graff, Caroline
Cattaneo, Antonio
Meli, Giovanni
Hamasaki, Maho
Nilsson, Per
Ankarcrona, Maria
Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title_full Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title_fullStr Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title_full_unstemmed Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title_short Amyloid β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer’s Disease-Related Models
title_sort amyloid β-peptide increases mitochondria-endoplasmic reticulum contact altering mitochondrial function and autophagosome formation in alzheimer’s disease-related models
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760163/
https://www.ncbi.nlm.nih.gov/pubmed/33260715
http://dx.doi.org/10.3390/cells9122552
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