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
Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States.
Front Cardiovasc Med. 2022 Feb 22;9:850538. doi: 10.3389/fcvm.2022.850538. eCollection 2022.
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.
能量产生途径中的进行性缺陷与多种衰老相关疾病有关，包括心血管疾病和阿尔茨海默病（AD）。然而，AD中心脏功能障碍的发病机制以及这两种器官疾病之间的关联仍需进一步阐明。本研究旨在表征AD模型中导致心脏功能下降的细胞缺陷。5XFAD小鼠是一种在人类APP和PS1中表达五个突变的品系，在2个月时显示出大量Aβ产生并伴有可见斑块，本研究将其用作AD模型。5XFAD小鼠和野生型（WT）对照在2个月、4个月和6个月时接受超声心动图检查，与WT相比，5XFAD的心脏缩短分数和射血分数显著降低。此外，5XFAD小鼠观察到的电信号降低，表现为R、P、T波振幅降低。在分离的心肌细胞中，5XFAD小鼠的缩短分数、缩短速率以及瞬时钙内流程度均降低。为了揭示AD导致心脏收缩功能障碍的机制，免疫印迹分析显示5XFAD左心室和脑组织中AMP激活的蛋白激酶（AMPK）的激活增加，表明能量代谢改变。线粒体应激试验检测线粒体功能发现，5XFAD心脏和大脑的基础和最大耗氧率降低，丙酮酸脱氢酶活性存在缺陷。5XFAD心脏和大脑中引发了细胞炎症，表现为活性氧积累增加和炎症介质活性上调。最后，在6个月大的5XFAD小鼠中观察到AD病理表型，Aβ沉积增加且认知功能缺陷。此外，在6个月大的5XFAD心脏中观察到纤维化增加。结果表明，AD导致线粒体功能缺陷和炎症增加，从而导致心脏收缩力下降。
