Mitochondrial calcium uptake in Alzheimer's disease

摘要： 阿尔茨海默病(AD)的特征是记忆丧失并伴有神经细胞死亡和 代谢功能障碍。许多研究已经报道了神经细胞内钙离子的失调。 (iCa+)信号转导是AD发病机制中的早期事件。据认为，神经元的长期抬高 钙离子促进线粒体钙的过度摄取，但到目前为止还没有研究检查 线粒体钙摄取在疾病进展中的作用。由于mCa~(2+)流量是细胞内重要的调节因子 呼吸和细胞死亡，这两个都与AD的发病有关，我们假设mCa~(2+) 超负荷是AD病理的关键因素，并可能导致代谢缺陷和神经元死亡。 为了确定线粒体钙交换在阿尔茨海默病中的作用，我们建立了3xTg-AD突变小鼠，小鼠具有神经元特异性 线粒体钙单一转运体(MCU)的缺失，这是线粒体摄取钙所必需的。此外，我们还有 产生了一个功能获得突变的小鼠，表达了最近发现的线粒体钙单转运体 β亚基(MCUb)。MCUb最近被报道为mCa~(2+)摄取的负调节因子，我们已经 观察到其在AD中的表达发生了实质性变化。这些模型将允许因果实验 测试mCa~(2+)摄取是否推动AD的进展。将检查小鼠的记忆力改变，淀粉样变性， Tau-病理，氧化应激，突触和代谢功能。初步数据表明，线粒体钙摄取 过载会损害错误折叠的蛋白质和功能失调的线粒体的清除。因此，我们将 从机制上考察钙离子交换与自噬和有丝分裂途径之间的联系。 最好的情况是，拟议的研究将发现AD和相关线粒体的新治疗靶点 并提供培训和研究平台，促进PIS的自主研究事业。

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.