Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71130, USA.
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, 71103, USA.
Sci Rep. 2024 Jul 19;14(1):16715. doi: 10.1038/s41598-024-67638-x.
Alzheimer's Disease (AD) is a progressive neurodegenerative disease caused by the deposition of Aβ aggregates or neurofibrillary tangles. AD patients are primarily diagnosed with the concurrent development of several cardiovascular dysfunctions. While few studies have indicated the presence of intramyocardial Aβ aggregates, none of the studies have performed detailed analyses for pathomechanism of cardiac dysfunction in AD patients. This manuscript used aged APP/PS1 Tg and littermate age-matched wildtype (Wt) mice to characterize cardiac dysfunction and analyze associated pathophysiology. Detailed assessment of cardiac functional parameters demonstrated the development of diastolic dysfunction in APP/PS1 Tg hearts compared to Wt hearts. Muscle function evaluation showed functional impairment (decreased exercise tolerance and muscle strength) in APP/PS1 Tg mice. Biochemical and histochemical analysis revealed Aβ aggregate accumulation in APP/PS1 Tg mice myocardium. APP/PS1 Tg mice hearts also demonstrated histopathological remodeling (increased collagen deposition and myocyte cross-sectional area). Additionally, APP/PS1 Tg hearts showed altered mitochondrial dynamics, reduced antioxidant protein levels, and impaired mitochondrial proteostasis compared to Wt mice. APP/PS1 Tg hearts also developed mitochondrial dysfunction with decreased OXPHOS and PDH protein complex expressions, altered ETC complex dynamics, decreased complex activities, and reduced mitochondrial respiration. Our results indicated that Aβ aggregates in APP/PS1 Tg hearts are associated with defects in mitochondrial respiration and complex activities, which may collectively lead to cardiac diastolic dysfunction and myocardial pathological remodeling.
阿尔茨海默病（AD）是一种由 Aβ 聚集物或神经纤维缠结沉积引起的进行性神经退行性疾病。AD 患者主要通过并发几种心血管功能障碍来诊断。虽然少数研究表明心肌内存在 Aβ 聚集物，但没有一项研究对 AD 患者心脏功能障碍的发病机制进行详细分析。本文使用老年 APP/PS1 Tg 和同窝年龄匹配的野生型（Wt）小鼠来描述心脏功能障碍并分析相关的病理生理学。对心脏功能参数的详细评估表明，与 Wt 心脏相比，APP/PS1 Tg 心脏出现舒张功能障碍。肌肉功能评估显示 APP/PS1 Tg 小鼠的运动耐量和肌肉力量下降。生化和组织化学分析显示 APP/PS1 Tg 小鼠心肌中 Aβ 聚集物的积累。APP/PS1 Tg 小鼠心脏还表现出组织病理学重塑（胶原沉积增加和心肌细胞横截面积增加）。此外，与 Wt 小鼠相比，APP/PS1 Tg 心脏还表现出线粒体动力学改变、抗氧化蛋白水平降低以及线粒体蛋白稳态受损。APP/PS1 Tg 心脏还出现线粒体功能障碍，氧化磷酸化（OXPHOS）和 PDH 蛋白复合物表达减少，ETC 复合物动力学改变，复合物活性降低，以及线粒体呼吸减少。我们的结果表明，APP/PS1 Tg 心脏中的 Aβ 聚集物与线粒体呼吸和复合物活性缺陷有关，这可能共同导致心脏舒张功能障碍和心肌病理性重塑。
