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Mitochondrial dysfunction and tau pathology in Alzheimer's disease

阿尔茨海默病中的线粒体功能障碍和 tau 病理学

基本信息

批准号：
10805120
负责人：
Gail V. W. Johnson
金额：
$ 42.35万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-16 至 2025-09-15
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10805120
关键词：
3-Dimensional 3xTg-AD mouse Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Animals Attenuated Bilateral Bioenergetics Biological Models Biology Brain Cells Complex Data Data Set Dementia Development Disease Disease Progression Electron Transport Etiology Event Evolution Exhibits Future Genes Harvest Hippocampus Hypoxia Impairment Injections Intervention Investigation Light Link Measures Metabolic Metabolism Mitochondria Modeling Modification Morphology Mus Neuronal Dysfunction Neurons Nucleic Acids Oxidative Phosphorylation Oxidative Stress Pathogenesis Pathologic Pathology Photosensitizing Agents Production Proteins Proton Pump Proton-Motive Force Protons Reactive Oxygen Species Research Role Slice Study models Symptoms System Tauopathies Technology Testing Therapeutic Time Toxin abeta oligomer experimental study in vivo in vivo Model innovation insight macromolecule mitochondrial dysfunction mouse model neonatal brain new technology novel optogenetics oxidation oxidized lipid preservation prevent response spatiotemporal stress granule tau Proteins tau aggregation tau-1 therapeutic development tool wireless wireless implant

项目摘要

Alzheimer’s disease (AD) is the most common cause of dementia with no current interventions that halt or substantially slow disease progression. AD is a multifactorial disease characterized by impaired mitochondrial bioenergetics, oxidative stress, and tau pathology. These AD pathologies are interconnected, change over time, and correlate with neuronal dysfunction. Moreover, the hallmarks are dynamic and difficult to isolate experimentally, which makes assigning causation challenging and limits therapeutic development. This proposal uses novel optogenetic technology developed for hypoxic biology to address this gap and test if mitochondrial dysfunction and reactive oxygen species (ROS) production are causal for the progression of tau pathology. Our approach involves directly controlling mitochondrial function and ROS production using light, without interfering with metabolism or using irreversible toxins with off-target effects. The optogenetic tools mitochondria-ON (mtON) and mitochondria-OFF (mtOFF) are mitochondria-targeted light-activated proton pumps that alter mitochondrial bioenergetics to turn ‘on’ or ‘off’ mitochondrial function in response to light. Similarly, mtSuperNova is a mitochondria-targeted genetically-encoded photosensitizer which generates ROS in response to light. These tools will spatiotemporally control mitochondrial function and ROS production in both an ex vivo brain slice culture and an in vivo mouse model using the PS19 mouse line (P301S tau). These mice exhibit early mitochondrial dysfunction and have been used extensively to study tau pathology and are an optimal model for these studies. Organotypic brain slice cultures will be used to provide a three-dimensional system to mechanistically test when and how mitochondrial energetics and ROS production contribute to pathological tau modifications. AD is largely associated with aging; therefore, in we will bridge our ex vivo findings into an adult in vivo model. Using a wireless optogenetic system, we will illuminate hippocampi in live, freely moving PS19 adult mice to test the effect of mitochondrial dysfunction over time on measures of oxidative stress and tau pathology. Mitochondrial dysfunction and ROS production have long been associated with AD pathology however the cause-and-effect relationship is unclear. Our novel technology provides an approach to directly test the role of mitochondria in AD independent of confounding factors. Overall, these studies will begin to clearly define the role of mitochondria in the evolution of tau pathology and provide mechanistic insights into therapeutic opportunities to attenuate AD pathogenesis.

阿尔茨海默病（AD）是痴呆症的最常见原因，目前没有停止或大大减缓疾病进展。AD是一种多因素疾病，其特征在于线粒体受损生物能量学、氧化应激和tau病理学。这些AD病理是相互关联的，随着时间的推移而变化，并与神经元功能障碍有关。此外，这些特征是动态的，很难孤立出来实验上，这使得分配因果关系具有挑战性，并限制了治疗的发展。这项建议使用为缺氧生物学开发的新型光遗传学技术来解决这一差距，并测试线粒体功能障碍和活性氧（ROS）产生是tau病理学进展的原因。我们这种方法涉及使用光直接控制线粒体功能和ROS产生，而不干扰或使用具有脱靶效应的不可逆毒素。光遗传学工具ESPA-ON （mtON）和线粒体关闭（mtOFF）是靶向线粒体的光激活质子泵，线粒体生物能量学以响应于光而"打开"或"关闭"线粒体功能。同样，mtSuperNova 是一种靶向的基因编码光敏剂，对光有反应时产生ROS。这些这些工具将在离体脑切片培养物中时空控制线粒体功能和ROS产生，以及使用PS19小鼠系（P301S tau）的体内小鼠模型。这些小鼠表现出早期线粒体功能障碍，并已广泛用于研究tau病理学，是这些研究的最佳模型。器官型脑切片培养将用于提供三维系统，以机械地测试何时以及线粒体能量学和ROS产生如何促进病理性tau蛋白修饰。AD主要是与衰老相关;因此，我们将把我们的离体研究结果与成人体内模型联系起来。使用无线光遗传学系统，我们将在活的、自由移动的PS19成年小鼠中照射光营，以测试光遗传学系统的作用。随着时间的推移，线粒体功能障碍对氧化应激和tau病理学的测量。线粒体长期以来，功能障碍和ROS产生与AD病理学有关，关系不清楚。我们的新技术提供了一种直接测试线粒体在AD中作用的方法独立于混杂因素。总的来说，这些研究将开始明确定义线粒体在 tau病理学的演变，并提供对减轻AD的治疗机会的机制见解发病机制