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) 是痴呆症最常见的原因，目前尚无干预措施可以阻止或阻止 AD 是一种多因素疾病，其特征是线粒体受损。生物能量学、氧化应激和 tau 蛋白病理学是相互关联的，随着时间的推移而变化，并且与神经功能障碍相关，这些特征是动态的并且难以分离。实验性的，这使得确定因果关系具有挑战性并限制了治疗的发展。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是否功能障碍和活性氧 (ROS) 的产生是 tau 病理进展的原因。该方法涉及利用光直接控制线粒体功能和 ROS 产生，而不干扰与新陈代谢或使用具有脱靶效应的不可逆毒素的光遗传学工具线粒体-ON。 (mtON) 和线粒体关闭 (mtOFF) 是线粒体靶向光激活质子泵，可改变类似地，mtSuperNova 可以通过线粒体生物能量学来“打开”或“关闭”线粒体功能。是一种针对线粒体的基因编码光敏剂，可响应光产生 ROS。工具将在离体脑切片培养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，主要用于研究 tau 病理学，是这些研究的最佳模型。器官型脑切片培养物将用于提供三维系统，以机械测试何时线粒体能量学和 ROS 产生如何影响 AD 的病理性修饰。与衰老相关；因此，我们将使用无线将我们的离体发现与成人体内模型联系起来。光遗传学系统，我们将照亮活体、自由活动的PS19成年小鼠的海马体，以测试光遗传学系统的效果随着时间的推移，氧化应激和 tau 蛋白病理学测量导致线粒体功能障碍。功能障碍和 ROS 产生长期以来一直与 AD 病理相关，但因果关系我们的新技术提供了一种直接测试线粒体在 AD 中的作用的方法。总体而言，这些研究将开始明确线粒体在其中的作用。 tau 病理学的演变并为减轻 AD 的治疗机会提供机制见解发病。