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 TITLE=The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease JOURNAL=Frontiers in Cardiovascular Medicine VOLUME=Volume 9 - 2022 YEAR=2022 URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2022.850538 DOI=10.3389/fcvm.2022.850538 ISSN=2297-055X ABSTRACT=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 associa-tions between the two organ diseases need further elucidation. This study aims to char-acterize cellular defects resulting in decreased cardiac function in AD-model. 5xFAD mice, a strain expressing five mutations in human APP and PS1 show robust Aβ produc-tion 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 fraction shortening and ejection fraction compared to WT. Additionally, 5xFAD mice had decreased ob-served electrical signal demonstrated as decreased P, Q, 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 and ATP-production, as well as defected pyruvate dehydrogenase activity in 5xFAD heart and brain. Cellular inflammation was provoked in 5xFAD heart and brain marked by the increase of reactive oxygen species accumulation and upregulation of inflammatory media-tor activities. Finally, AD pathological phenotype with increased deposition of Aβ and defected cognitive function was observed in 6-month 5xFAD mice. In addition, elevated fibrosis was observed in a 6-month 5xFAD heart. The results implicated that AD led to defective mitochondrial function, decreased energy production, and increased inflammation which causes the decrease in contractility of the heart.