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

Jiayuan Murphy,Di Ren,Mohammad Kasim Fatmi,Linda Ines Zoungrana,Edward J Lesnefsky,Ji Li,Yi Yang,Meredith Krause-Hauch,Julia Fedorova,Kayla Davitt,Tran Ngoc Van Le

doi:10.3389/fcvm.2022.850538

Jiayuan Murphy, Di Ren + Show 9 more

Open Access

https://doi.org/10.3389/fcvm.2022.850538

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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.

Highlights

Alzheimer’s Disease (AD) is a common aging-related neurological disorder that manifests as impaired cognition, short-term memory loss, increased irritability, and personality changes [1, 2]
To achieve the goal of further illustrating the pathogenesis of cardiovascular dysfunction related to AD, we demonstrate in this study that a strain of AD model mice, 5 familial AD mutations (5XFAD) mice, has significantly worse cardiac outcomes such as decreased contractility and increased inflammatory markers caused by damage to mitochondrial function, possibly related to increased Aβ plaque deposition. 5XFAD mice overexpress the K670N/M671L (Swedish), I716V (Florida), and V717I (London) mutations in human Amyloid precursor protein (APP) [695], as well as M146L and L286V mutations in human Presenilin 1 (PS1)
To assess the changes in cardiac function related to AD, we utilized a strain of mice as a model for AD, 5XFAD, which carried five mutations resulting in early-onset AD around 6-month of age

Summary

Introduction

Alzheimer’s Disease (AD) is a common aging-related neurological disorder that manifests as impaired cognition, short-term memory loss, increased irritability, and personality changes [1, 2]. AD has numerous comorbidities, including several major cardiovascular diseases [4, 6, 7]. The interplay amongst these conditions is not yet clearly defined. They share one glaring similarity characterized by a significant increase in disease incidences onset in the elderly population, and aging is associated with worsening disease progression [8, 9]. One notable change is the reduction of energy uptake and utilization [10]. This metabolic impairment is both heavily implicated in AD and cardiovascular dysfunction [11, 12]. It has been proposed that the systematic reduction of metabolic activities and the consequences following are prominent causes for many agerelated diseases, including AD and cardiovascular disorders [13]

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