Joshi Amit U, Saw Nay L, Shamloo Mehrdad, Mochly-Rosen Daria
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Behavioral and Functional Neuroscience Laboratory, Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Oncotarget. 2017 Dec 22;9(5):6128-6143. doi: 10.18632/oncotarget.23640. eCollection 2018 Jan 19.
Mitochondrial dynamics, involving a balance between fusion and fission, regulates mitochondrial quality and number. Increasing evidence suggests that dysfunctional mitochondria play a role in Alzheimer's disease (AD). We observed that Drp1 interaction with one of the adaptors, Fis1, is significantly increased in Aβ-treated neurons and AD patient-derived fibroblasts. P110, a seven-amino acid peptide, which specifically inhibits Drp1/Fis1 interaction without affecting the interaction of Drp1 with its other adaptors, attenuated Aβ-induced mitochondrial recruitment of Drp1 and prevented mitochondrial structural and functional dysfunction in cultured neurons, in cells expressing mutant amyloid precursor protein (KM670/671NL), and in five different AD patient-derived fibroblasts. Importantly, sustained P110 treatment significantly improved behavioral deficits, and reduced Aβ accumulation, energetic failure and oxidative stress in the brain of the AD mouse model, 5XFAD. This suggests that Drp1/Fis1 interaction and excessive mitochondrial fission greatly contribute to Aβ-mediated and AD-related neuropathology and cognitive decline. Therefore, inhibiting excessive Drp1/Fis1-mediated mitochondrial fission may benefit AD patients.
线粒体动力学涉及融合与分裂之间的平衡，可调节线粒体的质量和数量。越来越多的证据表明，功能失调的线粒体在阿尔茨海默病（AD）中起作用。我们观察到，在经Aβ处理的神经元和AD患者来源的成纤维细胞中，动力蛋白相关蛋白1（Drp1）与衔接蛋白之一Fis1的相互作用显著增加。P110是一种七氨基酸肽，它能特异性抑制Drp1/Fis1相互作用，而不影响Drp1与其其他衔接蛋白的相互作用，在培养的神经元、表达突变淀粉样前体蛋白（KM670/671NL）的细胞以及五种不同的AD患者来源的成纤维细胞中，可减弱Aβ诱导的Drp1向线粒体的募集，并防止线粒体结构和功能障碍。重要的是，持续的P110治疗显著改善了AD小鼠模型5XFAD的行为缺陷，并减少了其大脑中的Aβ积累、能量衰竭和氧化应激。这表明Drp1/Fis1相互作用和过度的线粒体分裂在很大程度上导致了Aβ介导的和AD相关的神经病理学及认知衰退。因此，抑制过度的Drp1/Fis1介导的线粒体分裂可能对AD患者有益。
