Tau clearance and synaptic and cognitive function rescue by activation of mitochondrial clearance in tauopathy model

tau蛋白病模型中通过激活线粒体清除来挽救tau蛋白清除以及突触和认知功能

• 批准号: 10504329
• 负责人: Shirley ShiDu Yan
• 金额: $ 173.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504329
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Attenuated; Autophagocytosis; Biological; Blood Platelets; Brain; Cell Line; Cells; Cognition; Cognitive; Defect; Development; Disease; Enhancers; Environment; Exposure to; Foundations; Functional disorder; Genetic; Gliosis; Hippocampus (Brain); Human; Hybrids; Impaired cognition; In Vitro; Inflammation; Injury; Lead; Learning; Link; MAPT gene; Maintenance; Mediating; Memory; Memory impairment; Microglia; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Outcome Study; PINK1 gene; Pathogenesis; Pathologic; Pathology; Patients; Phagocytosis; Pharmacology; Play; Protein Isoforms; Quality Control; Role; Signal Transduction; Slice; Stress; Synapses; Synapsins; Synaptic Transmission; Synaptosomes; Tauopathies; Therapeutic; Therapeutic Agents; Toxic effect; Transgenic Mice; Validation; cognitive function; genetic manipulation; hTau Mice; human model; improved; in vivo; insight; loss of function; mitochondrial dysfunction; mouse model; neurofibrillary tangle formation; neuroinflammation; novel; novel therapeutics; preclinical evaluation; prevent; response; small molecule; synaptic failure; synaptic function; synaptic pruning; tau Proteins; tau aggregation; tau mutation; therapeutic target; translational impact

Summary: Microtubule associated protein tau (MAPT) plays a major role in Alzheimer’s disease (AD) and related disorder (ADRD) and have deleterious effects on mitochondrial and synaptic function and neuroinflammation. Tau oligomers, prior to neurofibrillary tangle (NFT) formation, are toxic species responsible for tau toxicity, mitochondrial and synaptic damage, and memory impairment. However, the underlying mechanisms of abnormal tau accumulation and strategies to eliminate them remain largely unknown. There is limited mechanistic study investigating the likely interplays between mitochondrial dysfunction and neuroinflammation and their contribution to synaptic damage and tauopathy in AD and related disorder (ADRD). PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control via mitophgy. PINK1 was significantly decreased in AD-affected brains, AD mice, including widely used tauopathy mice, suggesting defective mitophagy in AD and ADRD. Development and validation of biological activity of PINK1 enhancer remains to be explored. This proposal will address the fundamental unexplored questions of whether PINK1 is a key player in tau-related aberrant mitochondria and synaptic injury and mitochondria-mediated neuroinflammation and whether genetic and pharmacological enhancement of PINK1 proves beneficial for tau clearance, mitochondrial quality control, and cognitive function as a potential therapeutic strategy in AD and ADRD. We will elucidate PINK1-dependent new mechanisms underlying tau pathology and clearance, proper mitochondrial and synaptic function via PINK1/mitochondria/neuroinflammation axis relevant to the pathogenesis of neurodegeneration by employing PINK1 novel genetically manipulated transgenic mouse models and pharmacological PINK1 enhancer in tau-rich environment, and human neuronal cells containing patient AD- and non-AD-derived mitochondria.

概括： 微管相关蛋白tau（MAPT）在阿尔茨海默氏病（AD）和 相关障碍（ADRD），对线粒体和突触功能以及 神经炎症。 tau低聚物，在神经纤维缠结（NFT）形成之前，是有毒的 负责TAU毒性，线粒体和突触损伤以及记忆力障碍的物种。 但是，异常tau积累和消除策略的基本机制 他们仍然在很大程度上未知。机械研究有限研究可能的相互作用 线粒体功能障碍和神经炎症及其对突触的贡献之间 AD和相关障碍（ADRD）中的损害和tauopathy。 PTEN诱导的假定激酶1 （pink1）对于维持线粒体完整性和质量控制很重要 线粒体。在受广泛影响的大脑，AD小鼠中，PINK1显着降低了，包括广泛 使用的陶氏病小鼠，表明在AD和ADRD中有缺陷的线粒体。发展和 对PINK1增强剂的生物活性的验证仍有待探索。该提议将 解决了Pink1是否是与Tau有关的关键参与者的基本意外问题 异常线粒体和突触损伤以及线粒体介导的神经炎症和 PINK1的遗传和药物增强是否证明对Tau的清除有益， 线粒体质量控制和认知功能是AD和 adrd。我们将阐明tau病理学基础的pink1依赖性新机制 清除，通过PINK1/线粒体/神经炎症的正确线粒体和突触功能 通过使用PINK1新颖的遗传学，与神经退行性的发病机理有关 操纵的转基因小鼠模型和富含tau的药物Pink1增强剂 环境以及含有患者AD和非衍生的线粒体的人类神经元细胞。