Alzheimer’s disease is a common and devastating disease characterized by aggregation of the amyloid-β peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer’s disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-β proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-β proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer’s disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-β proteotoxic diseases, such as Alzheimer’s disease.

中文翻译：

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增强线粒体蛋白质稳态可降低淀粉样蛋白-β 的蛋白质毒性


阿尔茨海默病是一种常见的破坏性疾病，其特征是淀粉样β肽的聚集。然而，我们对潜在的分子机制或如何治疗阿尔茨海默病患者知之甚少。在这里，我们提供了生物信息学和实验证据，证明在人类、小鼠和秀丽隐杆线虫中涉及淀粉样蛋白-β蛋白毒性的疾病中存在保守的线粒体应激反应特征，涉及线粒体未折叠蛋白反应和线粒体自噬途径。使用淀粉样β蛋白毒性蠕虫模型GMC101，我们概括了线粒体特征，并证实这种线粒体应激反应的诱导对于维持线粒体蛋白质稳态和健康至关重要。值得注意的是，通过药理学和基因靶向线粒体翻译和线粒体自噬来增加线粒体蛋白质稳态，可以增加 GMC101 线虫的适应性和寿命，并减少细胞、线虫和阿尔茨海默病转基因小鼠模型中淀粉样蛋白的聚集。我们的数据支持增强线粒体蛋白质稳态与延缓淀粉样蛋白-β蛋白毒性疾病（例如阿尔茨海默氏病）的相关性。