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， 影响大脑。微管相关蛋白tau（Microtubule associated protein tau，MAPT）在AD中起主要作用，并具有有害作用 对线粒体和突触功能的影响异常Tau（包括Tau寡聚体）的积累导致 线粒体和突触损伤、炎症和记忆障碍。的潜在机制 异常的Tau积累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）是线粒体通透性转换形成中不可或缺的一部分 孔（mPTP），导致细胞死亡。CypD的缺失可防止Aβ诱导的线粒体和突触损伤。 然而，CypD在Tau介导的线粒体和Tau病理学中的作用尚未探索。在我们 初步研究发现，CypD在AD脑和Tau病模型中特异性地与tau相互作用。损失 CypD的表达有力地减少了过度磷酸化的Tau和Tau寡聚体，并恢复了线粒体和认知功能。 在人类突变型Tau小鼠中的功能。此外，CypD缺陷型Tau小鼠显示了抑制诱导的细胞凋亡。 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 功能障碍引起神经炎症，导致异常的tau代谢和清除。为了验证这一 假设，我们将研究CypD的阻断是否促进异常tau清除， 减少tau蛋白病，从而减轻AD中tau蛋白诱导的异常线粒体和认知下降。 利用新的遗传操纵的CypD-AD小鼠模型和具有改变的CypD水平的神经元培养物 在富含tau的环境和含有患者AD衍生线粒体的AD胞质杂交体中，我们将阐明CypD- Tau病理学、清除、线粒体改变和神经炎症的依赖性机制。

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.