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

Abstract

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.

Hepatic and cardiac implications of increased toxic amyloid-beta serum level in lipopolysaccharide-induced neuroinflammation in rats: new insights into alleviating therapeutic interventions

“…10. In a line with our results, (Stakos et al 2020;Cermakova et al 2015;Yeung et al 2014;Fioranelli et al 2018;Murphy et al 2022;Ewid et al 2020;Zhu et al 2022;Shen et al 2015) indicated that elevated Aβ serum level may be found to be associated with severe hypoxia, Fig. 8 Illustration of histopathological examination of cardiac tissues among subjected groups.…”

Diminished α7 nicotinic acetylcholine receptor (α7nAChR) rescues amyloid-β induced atrial remodeling by oxi-CaMKII/MAPK/AP-1 axis-mediated mitochondrial oxidative stress

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Targeting on Nrf2/Sesn2 Signaling to Rescue Cardiac Dysfunction during High-Fat Diet-Induced Obesity

“…The production of cardiac mitochondrial reactive oxygen species (ROS) was determined in both human LV tissues and mouse LV tissues using our previously described protocol [ 20 ]. Briefly, this was evaluated via wheat germ agglutinin (WGA) and MitoSOX Red staining.…”