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Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease

Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9)...

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Autores principales: Cuadrado-Tejedor, Mar, Pérez-González, Marta, Alfaro-Ruiz, Rocío, Badesso, Sara, Sucunza, Diego, Espelosin, María, Ursúa, Susana, Lachen-Montes, Mercedes, Fernández-Irigoyen, Joaquín, Santamaria, Enrique, Luján, Rafael, García-Osta, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584544/
https://www.ncbi.nlm.nih.gov/pubmed/34769380
http://dx.doi.org/10.3390/ijms222111950
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author Cuadrado-Tejedor, Mar
Pérez-González, Marta
Alfaro-Ruiz, Rocío
Badesso, Sara
Sucunza, Diego
Espelosin, María
Ursúa, Susana
Lachen-Montes, Mercedes
Fernández-Irigoyen, Joaquín
Santamaria, Enrique
Luján, Rafael
García-Osta, Ana
author_facet Cuadrado-Tejedor, Mar
Pérez-González, Marta
Alfaro-Ruiz, Rocío
Badesso, Sara
Sucunza, Diego
Espelosin, María
Ursúa, Susana
Lachen-Montes, Mercedes
Fernández-Irigoyen, Joaquín
Santamaria, Enrique
Luján, Rafael
García-Osta, Ana
author_sort Cuadrado-Tejedor, Mar
collection PubMed
description Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.
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spelling pubmed-85845442021-11-12 Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease Cuadrado-Tejedor, Mar Pérez-González, Marta Alfaro-Ruiz, Rocío Badesso, Sara Sucunza, Diego Espelosin, María Ursúa, Susana Lachen-Montes, Mercedes Fernández-Irigoyen, Joaquín Santamaria, Enrique Luján, Rafael García-Osta, Ana Int J Mol Sci Article Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice. MDPI 2021-11-04 /pmc/articles/PMC8584544/ /pubmed/34769380 http://dx.doi.org/10.3390/ijms222111950 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Cuadrado-Tejedor, Mar
Pérez-González, Marta
Alfaro-Ruiz, Rocío
Badesso, Sara
Sucunza, Diego
Espelosin, María
Ursúa, Susana
Lachen-Montes, Mercedes
Fernández-Irigoyen, Joaquín
Santamaria, Enrique
Luján, Rafael
García-Osta, Ana
Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title_full Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title_fullStr Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title_full_unstemmed Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title_short Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease
title_sort amyloid-driven tau accumulation on mitochondria potentially leads to cognitive deterioration in alzheimer’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584544/
https://www.ncbi.nlm.nih.gov/pubmed/34769380
http://dx.doi.org/10.3390/ijms222111950
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