PDF(Pubmed)
Abstract：
Alzheimer\'s disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.
摘要：
阿尔茨海默病（AD），老年人痴呆症最突出的形式，没有治愈方法。专注于减少淀粉样蛋白β或过度磷酸化Tau蛋白的策略在临床试验中大部分失败。迫切需要新的治疗目标和策略。新出现的数据表明，为了应对环境压力，线粒体启动综合应激反应（ISR），被证明对健康衰老和神经保护有益。这里,我们回顾了一些数据,这些数据表明,参与氧化磷酸化的线粒体电子传递复合物是小分子靶向治疗的中心,可以诱导有益的线粒体ISR.具体来说,线粒体复合物I的部分抑制已被用作多种人类疾病的新策略，包括AD,一些小分子正在临床试验中进行测试。我们讨论了目前对这种违反直觉的方法所涉及的分子机制的理解。由于这一战略也被证明可以提高健康和寿命，开发安全有效的复合物I抑制剂可以促进健康衰老，延缓与年龄相关的神经退行性疾病的发作。
