Qian Wenqiang, Liu Daozhou, Liu Jie, Liu Miao, Ji Qifeng, Zhang Bangle, Yang Zhifu, Cheng Ying, Zhou Siyuan
Department of Pharmaceutics, School of Pharmacy, Air Force Medical University, Xi'an, 710032, China.
Department of Pharmacy, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
Small. 2025 Feb;21(6):e2408581. doi: 10.1002/smll.202408581. Epub 2024 Dec 23.
Mitochondrial dysfunction plays an important role in neuroinflammation and cognitive impairment in Alzheimer's disease (AD). Herein, this work designs a mitochondria-targeted micelle CsA-TK-SS-31 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria-targeted peptide SS-31 drives cyclosporin A (CsA) to penetrate the blood-brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 × FAD mice. Under the high level of reactive oxygen species (ROS) environment in damaged mitochondria of microglia and neurons, the linker (thioketal, TK) between CsA and SS-31 is broken and CsA and SS-31 are released while consuming ROS in the microenvironment. The released CsA and SS-31 synergistically restore the mitochondrial membrane potential and the balance between the fission and fusion of mitochondria, which subsequently protect neurons from apoptosis and reduce the activation of microglia in the brains of 5 × FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 × FAD mice are ameliorated. This research provides a synergistic treatment strategy for AD through alleviating mitochondrial dysfunction to reduce neuroinflammation and restore the function of neurons simultaneously.
线粒体功能障碍在阿尔茨海默病（AD）的神经炎症和认知障碍中起重要作用。在此，本研究设计了一种线粒体靶向胶束CsA-TK-SS-31（CTS），通过同时减轻小胶质细胞和神经元中的线粒体功能障碍来阻断AD的进展。线粒体靶向肽SS-31驱动环孢素A（CsA）穿透血脑屏障（BBB），并将CsA递送至5×FAD小鼠大脑中的小胶质细胞和神经元的线粒体。在小胶质细胞和神经元受损线粒体的高活性氧（ROS）环境下，CsA与SS-31之间的连接子（硫代缩酮，TK）断裂，CsA和SS-31释放，同时消耗微环境中的ROS。释放的CsA和SS-31协同恢复线粒体膜电位以及线粒体分裂与融合之间的平衡，进而保护神经元免于凋亡，并减少5×FAD小鼠大脑中小胶质细胞的激活。最终，5×FAD小鼠的神经炎症和认知障碍得到改善。本研究通过减轻线粒体功能障碍以同时减少神经炎症和恢复神经元功能，为AD提供了一种协同治疗策略。
