Molecular signaling linking Alzheimer's disease and heart failure

项目总结： 阿尔茨海默病(AD)和心力衰竭(HF)是与年龄相关的疾病，会导致老年人大量死亡 病人。在AD患者中也有明显的心脏病理和功能障碍的报道，不同的 阿尔茨海默病小鼠模型。尽管进行了广泛的研究，但HF和AD之间的关系在很大程度上仍然不清楚。 我们开始对揭示Sigma-1受体(Sigmar1)蛋白在AD AS中的分子功能产生兴趣 研究表明：i)阿尔茨海默病患者死后样本中的Sigmar1结合位点减少，ii) Sigmar1的密度在AD早期降低，并且iii)Sigmar1的多态与改变相关 AD的风险。我们发现Sigmar1在体内和Sigmar1全局敲除小鼠体内都有丰富的表达 心脏显示线粒体呼吸受损，提示Sigmar1在细胞内具有潜在功能 新陈代谢。在父代的方案中，我们想要测试Sigmar1依赖的激活的中心假设 对代谢应激引起的心功能障碍和病理重塑具有保护作用。 为了确定Sigmar1在AD发病机制中的分子功能，我们将使用APPswe/PS1双链 表达人/鼠嵌合淀粉样前体蛋白的转基因小鼠(Mo/HuAPP695swe)和 突变型人早老素1(PS1-dE9)。APPswe/PS1小鼠AD病理模型包括 Aβ和磷酸化tau蛋白的积聚以及认知障碍也会发展 心肌细胞收缩功能障碍。在这里，我们将测试支持Sigmar1的中心假设 APPsWE/PS1小鼠AD模型的表达将减少A-β积聚和细胞损伤 大脑和心脏通过激活线粒体能量代谢。在这份阿尔茨海默氏症增刊中 我们将确定Sigmar1在Aβ积聚、认知功能障碍和心脏疾病中的作用 APPswe/PS1小鼠AD模型的功能障碍(Aim 1)并确定持续的Sigmar1依赖 线粒体能量代谢和功能恢复挽救AD发病机制和心功能不全 APP/PS1鼠标(目标2)。我们将结合使用分子、遗传和功能的综合方法 通过转基因小鼠来确定其直接参与并确定其分子机制 Sigmar1‘S在AD发病机制中的作用这项拟议的项目将确定一种新的治疗靶点 抗APPsWE/PS1诱导的代谢改变、线粒体功能障碍、细胞损伤和不良反应 病理性重构。

Project Summary: Alzheimer’s disease (AD) and heart failure (HF) are age-dependent diseases causing a substantial death in older patients. Pronounced cardiac pathology and dysfunction has also been reported in AD patients and different mouse model of AD. Despite extensive studies, the relationship between HF and AD remains largely unclear. We became interested in uncovering the molecular function of Sigma-1 receptor (Sigmar1) proteins in AD as studies showed that: i) Sigmar1 binding sites are reduced in postmortem samples from patients with AD, ii) the density of Sigmar1 is reduced in early AD, and iii) polymorphisms in Sigmar1 have been associated with altered risk for AD. We found that Sigmar1 is abundantly expressed in the body and Sigmar1 global knockout mouse heart showed impaired mitochondrial respiration suggesting a potential function of Sigmar1 in cellular metabolism. In the parent proposal, we wanted to test the central hypothesis that Sigmar1-dependent activation of metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling. To determine, the molecular function of Sigmar1 in AD pathogenesis, we will use the APPswe/PS1 double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9). The APPswe/PS1 mouse model having AD pathology, including accumulation of Aβ and phosphorylated tau proteins, as well as cognitive impairment and also develop cardiomyocyte contractile dysfunction. Here, we will test the central hypothesis that sustained Sigmar1 expression in the APPswe/PS1mouse model of AD will decrease the Aβ accumulation and cellular injury in the brain and heart through activation of mitochondrial energy metabolism. In this present Alzheimer’s supplement proposal, we will determine the role of Sigmar1 in Aβ accumulation, cognitive dysfunction and cardiac dysfunction in APPswe/PS1 mouse model of AD (Aim 1) and determine if sustained Sigmar1 dependent restoration of mitochondrial energy metabolism and function rescue AD pathogenesis and cardiac dysfunction APP/PS1 mouse (Aim 2). We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement and define the molecular mechanisms of Sigmar1’s role in AD pathogenesis. This proposed project will identify a novel therapeutic target in protecting against APPswe/PS1-induced metabolic alterations, mitochondrial dysfunction, cellular injury, and adverse pathological remodeling.