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.

总结： 微管相关蛋白tau（MAPT）在阿尔茨海默病（AD）中起主要作用， 相关疾病（ADRD），并对线粒体和突触功能产生有害影响， 神经炎症Tau寡聚体在神经元缠结（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障碍的物种。 然而，异常tau蛋白积累的潜在机制和消除tau蛋白积累的策略， 他们基本上仍不为人所知。有有限的机制研究调查可能的相互作用 线粒体功能障碍和神经炎症之间的关系及其对突触 AD及相关疾病（ADRD）中的损伤和tau蛋白病。PTEN诱导的推定激酶1 （PINK 1）对于维持线粒体的完整性和质量控制是重要的， 有丝分裂PINK 1在AD受影响的大脑，AD小鼠，包括广泛的 使用tau蛋白病小鼠，表明AD和ADRD中的线粒体自噬缺陷。发展和 PINK 1增强子的生物活性的验证仍有待探索。这项建议会 解决了PINK 1是否是tau相关的关键参与者的基本未探索的问题， 异常的线粒体和突触损伤以及神经细胞介导的神经炎症， PINK 1的遗传和药理学增强是否证明有益于tau清除， 线粒体质量控制和认知功能作为AD和 ADRD。我们将阐明PINK 1依赖的tau病理学基础的新机制， 通过PINK 1/线粒体/神经炎症清除、适当的线粒体和突触功能 轴相关的神经退行性变的发病机制，通过采用PINK 1新的遗传 操作的转基因小鼠模型和富含tau蛋白的药理学PINK 1增强子 环境和含有患者AD和非AD来源的线粒体的人神经元细胞。