Mitochondria modulate Tau pathology and neuroinflammation

项目摘要 线粒体功能障碍和突触损伤是阿尔茨海默病(AD)的早期病理特征。 受影响的大脑。微管相关蛋白tau(MAPT)在阿尔茨海默病(AD)中起重要作用，具有一定的毒副作用 线粒体和突触功能。异常牛磺酸的积累，包括牛磺酸低聚物，导致 线粒体和突触损伤、炎症和记忆障碍。其潜在机制是 Tau的异常蓄积和消除它们以恢复线粒体功能的策略在很大程度上仍然存在 未知。亲环素D(CypD)是线粒体通透性转变形成过程中不可或缺的一部分 毛孔(MPTP)，导致细胞死亡。CypD的缺失对Aβ诱导的线粒体和突触损伤具有保护作用。 然而，CypD在tau介导的线粒体和Tau病理中的作用尚不清楚。在我们的 初步研究发现，在阿尔茨海默病模型中，CypD与tau发生了特异性的相互作用。损失 CypD显著减少过度磷酸化的Tau和Tau寡聚体，恢复线粒体和认知功能 在人类突变的Tau小鼠中的作用。此外，CypD缺陷的Tau小鼠表现出抑制诱导 促炎介质。这些令人兴奋的结果使我们假设CypD介导的线粒体 功能障碍会引发神经炎症，导致tau代谢和清除异常。为了测试这一点 假设，我们将调查CypD的阻断是否因此促进了异常的tau清除 减少tautation，从而减轻tau诱导的AD患者的线粒体异常和认知能力下降。 利用新的基因操作的CypD-AD小鼠模型和改变CypD水平的神经元培养 在tau丰富的环境中，以及含有患者AD来源线粒体的AD胞质中，我们将阐明CypD- Tau病理、清除、线粒体改变和神经炎症的相关机制。

Project Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer's disease (AD)- affected brain. Microtubule associated protein tau (MAPT) plays a major role in AD and have deleterious effects on mitochondrial and synaptic function. Accumulation of abnormal Tau, including Tau oligomers, causes mitochondrial and synaptic damage, inflammation, and memory impairment. The underlying mechanisms of abnormal Tau accumulation and strategies to eliminate them to restore mitochondrial function remain largely unknown. Cyclophilin D (CypD) is an integral part in the formation of the mitochondrial permeability transition pore (mPTP), leading to cell death. Loss of CypD protects against Aβ-induced mitochondrial and synaptic injury. However, the role of CypD in tau-mediated mitochondrial and Tau pathology has not been explored. In our preliminary studies, we found that CypD specifically interacts with tau in AD brains and Tauopathy model. Loss of CypD robustly reduced hyperphosphorylated Tau and Tau oligomers and restored mitochondrial and cognitive function in human mutant Tau mice. Furthermore, CypD-deficient Tau mice revealed suppression of induction of proinflammatory mediators. These exciting results lead us to hypothesize that CypD-mediated mitochondrial dysfunction provokes neuroinflammation, contributing to abnormal tau metabolism and clearance. To test this hypothesis, we will investigate whether blockade of CypD promotes abnormal tau clearance consequently reducing tauopathy and thereby alleviating tau-induced aberrant mitochondrial and cognitive decline in AD. Utilizing novel genetically manipulated CypD-AD mouse models and neuronal culture with altered CypD levels in tau-rich environment, and AD cybrids containing patient AD-derived mitochondria, we will elucidate CypD- dependent mechanisms underlying Tau pathology, clearance, mitochondrial alterations, and neuroinflammation.