The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease.
The Cardiac Dysfunction Caused by Metabolic Alterations in Alzheimer's Disease.
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DOI：
10.3389/fcvm.2022.850538
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发表时间：
2022
影响因子：
3.6
通讯作者：
Ren D
中科院分区：
文献类型：
--
作者：
Murphy J;Le TNV;Fedorova J;Yang Y;Krause-Hauch M;Davitt K;Zoungrana LI;Fatmi MK;Lesnefsky EJ;Li J;Ren D
能量生成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心功能不全的发病机制和两种器官疾病之间的关联的证据需要进一步阐明。本研究旨在表征AD模型中导致心脏功能降低的细胞缺陷。5XFAD小鼠，一种在人APP和PS1中表达5个突变的品系，在2个月时显示出稳健的Aβ产生和可见的斑块，并在本研究中用作AD模型。在2个月、4个月和6个月时对5XFAD小鼠和野生型（WT）小鼠进行超声心动图检查，与WT相比，5XFAD小鼠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减少，表现为R、P、T波振幅降低。在分离的心肌细胞中，5XFAD小鼠显示缩短分数、缩短率以及瞬时钙内流程度降低。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活化蛋白激酶（AMPK）的活化增加，表明能量代谢改变。检查线粒体功能的Mito应激试验显示，5XFAD心脏和大脑中的基础和最大耗氧率降低，以及丙酮酸脱氢酶活性缺陷。在5XFAD心脏和大脑中引起细胞炎症，其特征在于活性氧积累的增加和炎症介质活性的上调。最后，在6个月的5XFAD小鼠中观察到AD病理表型，Aβ沉积增加和认知功能缺陷。此外，在6个月5XFAD心脏中观察到纤维化升高。结果表明，AD导致线粒体功能缺陷，炎症增加，导致心脏收缩力下降。
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.