Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer's disease.
Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer's disease.
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阿尔茨海默病 APPsw/ PS1dE9 小鼠模型中线粒体动力学随年龄变化
DOI：
10.1097/wnr.0000000000000739
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发表时间：
2017-03-01
期刊：
影响因子：
1.7
通讯作者：
Bi JZ
中科院分区：
文献类型：
--
作者：
Xu LL;Shen Y;Wang X;Wei LF;Wang P;Yang H;Wang CF;Xie ZH;Bi JZ
越来越多的研究表明，线粒体缺陷在阿尔茨海默病（AD）的发病机制中起着重要作用。我们的目的是更好地了解线粒体的变化与AD的发展和进展。我们比较了作为AD动物模型的3、6、9和12月龄的APPsw/PS1 dE 9转基因小鼠和作为对照的年龄匹配的C57 BL/6小鼠。APPsw/PS1 dE 9小鼠的学习能力和空间记忆能力与对照组相比差异有统计学意义（P < 0. 05）。从第3个月开始，APPsw/PS1 dE 9小鼠海马组织线粒体形态发生改变。“髓小体”，这是由大量的变性和破碎的线粒体在神经髓鞘中的积累而形成的，可能是AD晚期在电子显微镜上观察到的特征性变化。此外，线粒体融合蛋白（视神经萎缩1和mitofusin 2）和裂变蛋白（动力蛋白相关蛋白1和裂变1）的水平在转基因小鼠与对照组相比，AD的进展。我们发现在3个月时APP/PS1小鼠的分裂和融合蛋白水平增加，表明异常线粒体动力学的存在可能是早期AD进展中的事件。通过改良Morris水迷宫试验测量，线粒体的变化先于记忆衰退的发作。线粒体动力学异常可作为AD早期诊断和病情监测的指标。需要进一步的研究来研究AD中控制线粒体分裂/融合的信号通路。
Increasing research suggests that mitochondrial defects play a major role in Alzheimer’s disease (AD) pathogenesis. We aimed to better understand changes in mitochondria with the development and progression of AD. We compared APPsw/PS1dE9 transgenic mice at 3, 6, 9, and 12 months old as an animal model of AD and age-matched C57BL/6 mice as controls. The learning ability and spatial memory ability of APPsw/PS1dE9 mice showed significant differences compared with controls until 9 and 12 months. Mitochondrial morphology was altered in hippocampus tissue of APPsw/PS1dE9 mice beginning from the third month. ‘Medullary corpuscle’, which is formed by the accumulation of a large amount of degenerative and fragmented mitochondria in neuropils, may be the characteristic change observed on electron microscopy at a late stage of AD. Moreover, levels of mitochondrial fusion proteins (optic atrophy 1 and mitofusin 2) and fission proteins (dynamin-related protein 1 and fission 1) were altered in transgenic mice compared with controls with progression of AD. We found increased levels of fission and fusion proteins in APP/PS1 mice at 3 months, indicating that the presence of abnormal mitochondrial dynamics may be events in early AD progression. Changes in mitochondrial preceded the onset of memory decline as measured by the modified Morris water maze test. Abnormal mitochondrial dynamics could be a marker for early diagnosis of AD and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in AD.