Kimura Nobuyuki, Imamura Osamu, Ono Fumiko, Terao Keiji
Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan.
J Neurosci Res. 2007 Oct;85(13):2909-16. doi: 10.1002/jnr.21408.
Impaired axonal transport may promote pathogenesis in neurodegenerative disorders, such as Alzheimer's disease (AD). We previously showed that tau, amyloid precursor protein (APP), and intracellular amyloid beta-protein (Abeta) accumulate in the nerve-ending fraction of aged monkey brains, perhaps because of impaired axonal transport. In the present study, we assessed age-related changes of axonal transport motor proteins in aged monkey brains. Western blotting showed that kinesin, dynein, and dynactin (DYN) localizations dramatically changed with aging, and dynein level in nerve-ending fractions increased significantly. Coimmunoprecipitation analyses showed that DYN-dynein intermediate chain (DIC) interactions decreased, suggesting that age-related attenuation of this interaction may cause the impairment of dynein function. Moreover, RNAi-induced down-regulation of DIC in human neuroblastoma cells caused endogenous tau and APP to accumulate, and their subcellular localizations were also affected. Our findings suggest that aging attenuates DYN-DIC interaction, representing one of the risk factors for age-related impaired dynein function and even for accumulation of disease proteins.
轴突运输受损可能会促进神经退行性疾病（如阿尔茨海默病，AD）的发病机制。我们之前发现，在老年猴脑的神经末梢部分，tau蛋白、淀粉样前体蛋白（APP）和细胞内淀粉样β蛋白（Aβ）会积累，这可能是由于轴突运输受损所致。在本研究中，我们评估了老年猴脑中轴突运输运动蛋白与年龄相关的变化。蛋白质免疫印迹法显示，随着年龄增长，驱动蛋白、动力蛋白和发动蛋白（DYN）的定位发生了显著变化，神经末梢部分的动力蛋白水平显著升高。免疫共沉淀分析表明，DYN与动力蛋白中间链（DIC）的相互作用减弱，这表明这种与年龄相关的相互作用减弱可能会导致动力蛋白功能受损。此外，在人神经母细胞瘤细胞中，RNA干扰诱导的DIC下调导致内源性tau蛋白和APP积累，并且它们的亚细胞定位也受到影响。我们的研究结果表明，衰老会减弱DYN-DIC相互作用，这是与年龄相关的动力蛋白功能受损甚至疾病蛋白积累的危险因素之一。
