Alzheimer's disease (AD) is a neurodegenerative disease associated with the accumulation of amyloid-beta oligomers (AβO). Recent studies have demonstrated that mitochondria-specific autophagy (mitophagy) contributes to mitochondrial quality control by selectively eliminating the dysfunctional mitochondria. Mitochondria motility, which is regulated by Miro1, is also associated with neuronal cell functions. However, the role played by Miro1 in the mitophagy mechanism, especially relative to AβO and neurodegenerative disorders, remains unknown. In this study, AβO induced mitochondrial dysfunction, enhanced Parkin-mediated mitophagy, and reduced mitochondrial quantities in hippocampal neuronal cells (HT-22 cells). We demonstrated that AβO-induced mitochondrial fragmentation could be rescued to the elongated mitochondrial form and that mitophagy could be mitigated by the stable overexpression of Miro1 or by pretreatment with N-acetylcysteine (NAC)-a reactive oxygen species (ROS) scavenger-as assessed by immunocytochemistry. Moreover, using time-lapse imaging, under live cell-conditions, we verified that mitochondrial motility was rescued by the Miro1 overexpression. Finally, in hippocampus from amyloid precursor protein (APP)/presenilin 1 (PS1)/Tau triple-transgenic mice, we noted that the co-localization between mitochondria and LC3B puncta was increased. Taken together, these results indicated that up-regulated ROS, induced by AβO, increased the degree of mitophagy and decreased the Miro1 expression levels. In contrast, the Miro1 overexpression ameliorated AβO-mediated mitophagy and increased the mitochondrial motility. In AD model mice, AβO induced mitophagy in the hippocampus. Thus, our results would improve our understanding of the role of mitophagy in AD toward facilitating the development of novel therapeutic agents for the treatment of AβO-mediated diseases.

中文翻译：

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淀粉样β低聚物通过减少Miro1诱导帕金介导的线粒体吞噬。

阿尔茨海默氏病（AD）是与淀粉样β低聚物（AβO）积累相关的神经退行性疾病。最近的研究表明，线粒体特有的自噬（线粒体）通过选择性消除功能异常的线粒体而有助于线粒体质量控制。Miro1调节的线粒体运动性也与神经元细胞功能有关。然而，Miro1在线粒体机制中所起的作用，尤其是相对于AβO和神经退行性疾病而言，仍是未知的。在这项研究中，AβO诱导了海马神经元细胞（HT-22细胞）的线粒体功能障碍，增强了Parkin介导的线粒体吞噬，并减少了线粒体的数量。我们证明，AβO诱导的线粒体片段可以挽救为细长的线粒体形式，并且可以通过稳定的Miro1过表达或通过N-乙酰半胱氨酸（NAC）-一种活性氧（ROS）清除剂的预处理来减轻线粒体通过免疫细胞化学。此外，使用延时成像，在活细胞条件下，我们证实了Miro1过表达可以挽救线粒体的活力。最后，在来自淀粉样蛋白前体蛋白（APP）/早老素1（PS1）/ Tau三重转基因小鼠的海马中，我们注意到线粒体和LC3B点之间的共定位增加了。综上所述，这些结果表明由AβO诱导的ROS上调增加了线粒体的程度并降低了Miro1的表达水平。相反，Miro1的过表达改善了AβO介导的线粒体吞噬并增加了线粒体的运动性。在AD模型小鼠中，AβO诱导海马的线粒体吞噬。因此，我们的结果将增进我们对线粒体在AD中的作用的理解，以促进开发用于治疗AβO介导的疾病的新型治疗剂。