RAGE, mitochondria, and tau pathology in AD

项目摘要/摘要 线粒体和突触功能障碍是阿尔茨海默病(AD)的早期病理特征 大脑。生物能量学功能紊乱，呼吸衰竭，线粒体动力学异常，以及 在大脑和周围组织中观察到活性氧物种(ROS)的水平，包括血小板 阿尔茨海默病患者。RAGE(高级糖基化终末产物受体，AGEs)起信号作用 转导AGEs、S100/钙颗粒或淀粉样β蛋白(A？)的细胞表面受体位点。的交互作用 RAGE及其配体增加氧化应激、炎症、Aβ积聚并损害突触功能 和学习记忆。然而，RAGE对tau和Aβ介导的线粒体应激的影响 阿尔茨海默病的病理、tau诱导的突触和认知功能障碍仍不清楚。目前尚不清楚是否以及如何 RAGE依赖的信号转导有助于AD患者线粒体结构和功能的改变。 拟议中的研究将检验RAGE作为干扰线粒体的信号转导功能的假设 结构和功能，以及氧化应激，导致突触线粒体和突触功能障碍。这 该提案将解决愤怒是否是AD相关异常的关键角色这一根本问题 线粒体和突触损伤，以及阻断RAGE是否恢复线粒体和神经元功能。

PROJECT SUMMARY/ABSTRACT Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer's disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. RAGE (Receptor for Advanced Glycation Endproducts, AGEs) functions as a signal transducing cell surface acceptor site for AGEs, S100/calgranuline, or amyloid-beta peptide (Aß). Interaction of RAGE and its ligands increases oxidative stress, inflammation, Aβ accumulation, and impairs synaptic function and learning memory. However, the impact of RAGE on tau- and Aβ-mediated mitochondrial stress, tau pathology, tau-induced synaptic and cognitive dysfunction in AD remains unclear. It is unclear whether and how RAGE-dependent signal transduction contributes to alterations in mitochondrial structure and function in AD. The proposed studies will test the hypothesis that RAGE functions as signal transduction to perturb mitochondrial structure and function, and oxidative stress, leading to synaptic mitochondrial and synaptic dysfunction. This proposal will address the fundamental questions of whether RAGE is a key player in AD-related aberrant mitochondria and synaptic injury and whether blockade of RAGE restores mitochondrial and neuronal function.