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。 (1)钙信号转导是AD发病机制中的早期事件。据认为，神经元1Ca~(2+)的持续升高 促进线粒体钙的过度摄取，但到目前为止还没有研究证实这一作用 线粒体钙摄取与疾病进展的关系。由于mCa~(2+)流量是细胞呼吸的重要调节因子 细胞死亡，这两个都参与了AD的发病，我们假设mCa2+超载是一个关键 导致AD病理改变，并可能导致代谢缺陷和神经元死亡。定义…的角色 我们已经产生了3xTg-AD突变小鼠，其神经元特异性缺失了 线粒体钙统一转运体(MCU)，这是线粒体钙摄取所必需的。此外，我们还生成了一个 表达最近发现的线粒体钙单转运体β亚基的功能获得突变小鼠 (MCUb)。MCUb最近被报道为mCa~(2+)摄取的负调节因子，我们观察到 它在AD中的表达发生了实质性的变化。这些模型将允许因果实验来测试mCa2+ 摄取推动AD的进展。将检查小鼠的记忆变化，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，mCa~(2+)摄取过载会损害 清除错误折叠的蛋白质和功能失调的线粒体。因此，我们将机械地审查 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和相关线粒体功能障碍的新治疗靶点，并提供培训 和研究平台，推动PIS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 (1Ca2+) signaling as an early event in AD pathogenesis. It is thought that a prolonged elevation in neuronal 1Ca2+ 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.