RAGE, mitochondria, and tau pathology in AD

项目概要/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， 个脑袋生物能量学功能紊乱，呼吸衰竭，线粒体动力学异常， 在脑和外周组织中观察到活性氧（ROS）水平， AD患者。晚期糖基化终产物受体（Receptor for Advanced Glycation Endproducts，AGEs）是一种 转导AGEs、S100/钙颗粒蛋白或淀粉样β肽（A β）的细胞表面受体位点。相互作用 β-淀粉样蛋白及其配体增加氧化应激、炎症、Aβ积聚，并损害突触功能 学习记忆。然而，研究表明，tau蛋白对tau蛋白和Aβ介导的线粒体应激的影响， 病理学方面，AD中tau诱导的突触和认知功能障碍仍不清楚。目前还不清楚是否以及如何 RAGE依赖的信号转导有助于AD中线粒体结构和功能的改变。 这项研究将验证这一假设，即线粒体膜电位作为信号转导的功能，扰乱线粒体 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 该提案将解决以下基本问题：在与广告相关的异常行为中， 线粒体和突触损伤，以及阻断线粒体和突触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.