Mitochondrial dysfunction and tau pathology in Alzheimer's disease

阿尔茨海默病(AD)是痴呆症最常见的原因，目前没有任何干预措施阻止或 大大延缓了疾病的发展。AD是一种以线粒体受损为特征的多因素疾病 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相关。此外，这些特征是动态的，很难分离出来 在实验上，这使得确定因果关系具有挑战性，并限制了治疗的发展。这项建议 使用为低氧生物开发的新的光基因技术来解决这一差距，并测试线粒体 功能障碍和活性氧(ROS)的产生是tau病理进展的原因。我们的 该方法包括利用光直接控制线粒体功能和ROS产生，而不干扰 与新陈代谢或使用不可逆的毒素与目标外的影响。光遗传工具线粒体-on (Mton)和线粒体关闭(MtOFF)是线粒体靶向的光激活质子泵，可以改变 线粒体生物能量学：开启或关闭线粒体对光的反应功能。同样，mtSuperNova 是一种线粒体靶向的基因编码光敏剂，它能产生ROS对光做出反应。这些 工具将在时空上控制体外脑片培养中线粒体的功能和ROS的产生 以及使用PS19小鼠系(P301S Tau)建立的活体小鼠模型。这些小鼠表现出早期的线粒体 已被广泛用于研究tau的病理学，是这些研究的最佳模型。 器官型脑片培养将被用来提供一个三维系统来机械地测试何时 以及线粒体能量学和ROS产生如何有助于病理性tau修饰。广告很大程度上 因此，我们将把我们的体外研究结果与成人体内模型联系起来。使用无线网络 光遗传系统，我们将照亮活体、自由活动的PS19成年小鼠的海马区，以测试 氧化应激和tau病理指标随时间推移的线粒体功能障碍。线粒体 长期以来，功能障碍和ROS的产生一直与AD的病理有关，然而，因果关系 双方的关系尚不清楚。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 不受混杂因素的影响。总体而言，这些研究将开始明确定义线粒体在 Tau病理的演变，并为减轻AD的治疗机会提供机械性见解 发病机制。

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.