Mitochondrial calcium uptake in Alzheimer's disease

摘要： 阿尔茨海默病（AD）的特征在于伴随神经元细胞死亡的记忆丧失， 代谢功能障碍许多研究报道了神经元细胞内钙离子的失调 (iCa2+）信号传导作为AD发病机制中的早期事件。据认为，神经元的长期升高 iCa 2+促进线粒体钙（mCa 2+）的过度摄取，但迄今为止还没有研究表明， mCa 2+摄取对疾病进展的贡献。由于mCa 2+通量是细胞内钙离子浓度的重要调节因子， 呼吸和细胞死亡，这两者都参与了AD的发病机制，我们假设mCa 2 + 超负荷是AD病理学的关键因素，并可能导致代谢缺陷和神经元死亡。 为了确定mCa 2+交换在AD中的作用，我们产生了具有神经元特异性的3xTg-AD突变小鼠。 线粒体钙单向转运蛋白（MCU）缺失，这是mCa 2+摄取所必需的。另外我们有 产生了一个功能获得突变小鼠表达最近确定的线粒体钙单向转运体 β亚单位（MCUb）。最近有报道称，MCUB是mCa 2+摄取的负调节剂， 在AD中观察到其表达的实质性变化。这些模型将允许因果实验， 测试mCa 2+摄取是否驱动AD进展。将检查小鼠的记忆改变、淀粉样变性， tau病理学、氧化应激、突触和代谢功能。初步数据表明，mCa 2+摄取 超负荷损害错误折叠的蛋白质和功能障碍的线粒体的清除。所以我们会 机械地检查mCa 2+交换与自噬和线粒体吞噬途径之间的联系。 最理想的是，拟议的研究将发现AD和相关线粒体的新治疗靶点。 并提供一个培训和研究平台，以促进PI的独立研究生涯。

Abstract: Alzheimer's disease (AD) is characterized by the loss of memory accompanied by neuronal cell death and metabolic dysfunction. Numerous studies have reported a dysregulation in neuronal intracellular calcium (iCa2+) signaling as an early event in AD pathogenesis. It is thought that a prolonged elevation in neuronal iCa2+ promotes excessive mitochondrial calcium (mCa2+) uptake, yet to date no study has examined the contribution of mCa2+ uptake to disease progression. Since mCa2+ flux is an important regulator of cellular respiration and cell death, both of which are involved in AD pathogenesis, we hypothesize that mCa2+ overload is a key contributor to AD pathology and may contribute to metabolic deficits and neuronal demise. To define the role of mCa2+ exchange in AD we have generated 3xTg-AD mutant mice with neuronal-specific deletion of Mitochondrial Calcium Uniporter (MCU), which is required for mCa2+ uptake. In addition, we have generated a gain-of-function mutant mouse expressing the recently identified mitochondrial calcium uniporter beta subunit (MCUb). MCUb was recently reported as a negative regulator of mCa2+ uptake and we have observed substantial changes in its expression in AD. These models will allow causative experimentation to test if mCa2+ uptake drives AD progression. Mice will be examined for alterations in memory, amyloidosis, tau-pathology, oxidative stress, synaptic and metabolic function. Preliminary data suggest that mCa2+ uptake overload impairs the clearance of misfolded proteins and dysfunctional mitochondria. Therefore, we will mechanistically examine the link between mCa2+ exchange and autophagic and mitophagic pathways. Optimally, the proposed studies will discover new therapeutic targets for AD and associated mitochondrial dysfunction and provide a training and research platform to promote the PIs independent research career.