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The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease

A progressive defect in the energy generation pathway is implicated in multiple aging-related diseases, including cardiovascular conditions and Alzheimer's Disease (AD). However, evidence of the pathogenesis of cardiac dysfunction in AD and the associations between the two organ diseases need f...

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Autores principales: Murphy, Jiayuan, Le, Tran Ngoc Van, Fedorova, Julia, Yang, Yi, Krause-Hauch, Meredith, Davitt, Kayla, Zoungrana, Linda Ines, Fatmi, Mohammad Kasim, Lesnefsky, Edward J., Li, Ji, Ren, Di
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902161/
https://www.ncbi.nlm.nih.gov/pubmed/35274014
http://dx.doi.org/10.3389/fcvm.2022.850538
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author Murphy, Jiayuan
Le, Tran Ngoc Van
Fedorova, Julia
Yang, Yi
Krause-Hauch, Meredith
Davitt, Kayla
Zoungrana, Linda Ines
Fatmi, Mohammad Kasim
Lesnefsky, Edward J.
Li, Ji
Ren, Di
author_facet Murphy, Jiayuan
Le, Tran Ngoc Van
Fedorova, Julia
Yang, Yi
Krause-Hauch, Meredith
Davitt, Kayla
Zoungrana, Linda Ines
Fatmi, Mohammad Kasim
Lesnefsky, Edward J.
Li, Ji
Ren, Di
author_sort Murphy, Jiayuan
collection PubMed
description A progressive defect in the energy generation pathway is implicated in multiple aging-related diseases, including cardiovascular conditions and Alzheimer's Disease (AD). However, evidence of the pathogenesis of cardiac dysfunction in AD and the associations between the two organ diseases need further elucidation. This study aims to characterize cellular defects resulting in decreased cardiac function in AD-model. 5XFAD mice, a strain expressing five mutations in human APP and PS1 that shows robust Aβ production with visible plaques at 2 months and were used in this study as a model of AD. 5XFAD mice and wild-type (WT) counterparts were subjected to echocardiography at 2-, 4-, and 6-month, and 5XFAD had a significant reduction in cardiac fractional shortening and ejection fraction compared to WT. Additionally, 5XFAD mice had decreased observed electrical signals demonstrated as decreased R, P, T wave amplitudes. In isolated cardiomyocytes, 5XFAD mice showed decreased fraction shortening, rate of shortening, as well as the degree of transient calcium influx. To reveal the mechanism by which AD leads to cardiac systolic dysfunction, the immunoblotting analysis showed increased activation of AMP-activated protein kinase (AMPK) in 5XFAD left ventricular and brain tissue, indicating altered energy metabolism. Mito Stress Assays examining mitochondrial function revealed decreased basal and maximal oxygen consumption rate, as well as defective pyruvate dehydrogenase activity in the 5XFAD heart and brain. Cellular inflammation was provoked in the 5XFAD heart and brain marked by the increase of reactive oxygen species accumulation and upregulation of inflammatory mediator activities. Finally, AD pathological phenotype with increased deposition of Aβ and defective cognitive function was observed in 6-month 5XFAD mice. In addition, elevated fibrosis was observed in the 6-month 5XFAD heart. The results implicated that AD led to defective mitochondrial function, and increased inflammation which caused the decrease in contractility of the heart.
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spelling pubmed-89021612022-03-09 The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease Murphy, Jiayuan Le, Tran Ngoc Van Fedorova, Julia Yang, Yi Krause-Hauch, Meredith Davitt, Kayla Zoungrana, Linda Ines Fatmi, Mohammad Kasim Lesnefsky, Edward J. Li, Ji Ren, Di Front Cardiovasc Med Cardiovascular Medicine A progressive defect in the energy generation pathway is implicated in multiple aging-related diseases, including cardiovascular conditions and Alzheimer's Disease (AD). However, evidence of the pathogenesis of cardiac dysfunction in AD and the associations between the two organ diseases need further elucidation. This study aims to characterize cellular defects resulting in decreased cardiac function in AD-model. 5XFAD mice, a strain expressing five mutations in human APP and PS1 that shows robust Aβ production with visible plaques at 2 months and were used in this study as a model of AD. 5XFAD mice and wild-type (WT) counterparts were subjected to echocardiography at 2-, 4-, and 6-month, and 5XFAD had a significant reduction in cardiac fractional shortening and ejection fraction compared to WT. Additionally, 5XFAD mice had decreased observed electrical signals demonstrated as decreased R, P, T wave amplitudes. In isolated cardiomyocytes, 5XFAD mice showed decreased fraction shortening, rate of shortening, as well as the degree of transient calcium influx. To reveal the mechanism by which AD leads to cardiac systolic dysfunction, the immunoblotting analysis showed increased activation of AMP-activated protein kinase (AMPK) in 5XFAD left ventricular and brain tissue, indicating altered energy metabolism. Mito Stress Assays examining mitochondrial function revealed decreased basal and maximal oxygen consumption rate, as well as defective pyruvate dehydrogenase activity in the 5XFAD heart and brain. Cellular inflammation was provoked in the 5XFAD heart and brain marked by the increase of reactive oxygen species accumulation and upregulation of inflammatory mediator activities. Finally, AD pathological phenotype with increased deposition of Aβ and defective cognitive function was observed in 6-month 5XFAD mice. In addition, elevated fibrosis was observed in the 6-month 5XFAD heart. The results implicated that AD led to defective mitochondrial function, and increased inflammation which caused the decrease in contractility of the heart. Frontiers Media S.A. 2022-02-22 /pmc/articles/PMC8902161/ /pubmed/35274014 http://dx.doi.org/10.3389/fcvm.2022.850538 Text en Copyright © 2022 Murphy, Le, Fedorova, Yang, Krause-Hauch, Davitt, Zoungrana, Fatmi, Lesnefsky, Li and Ren. 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 Cardiovascular Medicine
Murphy, Jiayuan
Le, Tran Ngoc Van
Fedorova, Julia
Yang, Yi
Krause-Hauch, Meredith
Davitt, Kayla
Zoungrana, Linda Ines
Fatmi, Mohammad Kasim
Lesnefsky, Edward J.
Li, Ji
Ren, Di
The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title_full The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title_fullStr The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title_full_unstemmed The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title_short The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease
title_sort cardiac dysfunction caused by metabolic alterations in alzheimer's disease
topic Cardiovascular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902161/
https://www.ncbi.nlm.nih.gov/pubmed/35274014
http://dx.doi.org/10.3389/fcvm.2022.850538
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