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RAGE, mitochondria, and tau pathology in AD

AD 中的 RAGE、线粒体和 tau 病理学

基本信息

批准号：
10320076
负责人：
SHI FANG YAN
金额：
$ 59.42万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320076
关键词：
Address Affect Age Alzheimer&apos s Disease Amyloid beta-Protein Attenuated Axon Biochemical Bioenergetics Blood Platelets Brain Cell Line Cell Surface Receptors Cell surface Chronic Cognitive Complex Data Defect Disease Disease Progression Exhibits Failure Functional disorder Hybrids Impaired cognition Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury Knockout Mice Lead Learning Ligands Link MAPT gene Mediating Mediator of activation protein Memory Memory impairment Microglia Mitochondria Mitochondrial Diseases Morphology Movement Mus Neurons Oxidative Stress Pathogenesis Pathologic Pathology Patients Peripheral Play Production Reactive Oxygen Species Regulation Research Respiration Role Signal Transduction Site Stimulus Stress Structure Synapses Tauopathies Testing Tissues Toxic effect Transducers Transgenic Mice Transgenic Organisms abeta accumulation age related cellular transduction cognitive function feasibility research human model improved in vivo insight mitochondrial dysfunction mutant neurofibrillary tangle formation neuroinflammation novel receptor expression receptor for advanced glycation endproducts synaptic function tau Proteins tau aggregation tau mutation tau phosphorylation therapeutic target trafficking transcription factor

项目摘要

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.

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。