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.

摘要： 微管相关蛋白tau在阿尔茨海默病中起重要作用 相关疾病(ADRD)和对线粒体和突触功能的有害影响以及 神经炎。在神经纤维缠结(NFT)形成之前，tau寡聚体是有毒的 造成tau毒性、线粒体和突触损伤以及记忆障碍的物种。 然而，tau异常蓄积的潜在机制和消除策略 它们在很大程度上仍不为人所知。对可能的相互作用进行了有限的机械研究。 线粒体功能障碍与神经炎症及其在突触中的作用 阿尔茨海默病及相关障碍的损害和肌张力障碍(ADRD)。PTEN诱导的可能的蛋白激酶1 (PINK1)是维持线粒体完整性和质量控制的重要途径 有丝分裂。PINK1在阿尔茨海默病大鼠大脑中显著降低，包括广泛的 使用紧张症小鼠，表明AD和ADRD有丝分裂吞噬缺陷。发展和 PINK1增强子的生物活性验证仍有待探索。这项提议将 解决尚未探索的基本问题，即PINK1是否是tau相关的关键参与者 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有利于tau清除， 线粒体质量控制和认知功能作为AD和AD的潜在治疗策略 阿德勒。我们将阐明依赖PINK1的新机制潜在的tau病理和 通过PINK1/线粒体/神经炎症清除、正常线粒体和突触功能 利用新的PINK1基因研究与神经变性发病机制相关的轴 富含tau基因的转基因小鼠模型及药理PINK1增强子的研究 环境，以及含有患者AD和非AD来源的线粒体的人类神经细胞。