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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model
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Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model

机译：阿尔茨海默氏病小鼠模型中突触线粒体的早期缺陷

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摘要

Synaptic dysfunction and the loss of synapses are early pathological features of Alzheimer's disease (AD). Synapses are sites of high energy demand and extensive calcium fluctuations; accordingly, synaptic transmission requires high levels of ATP and constant calcium fluctuation. Thus, synaptic mitochondria are vital for maintenance of synaptic function and transmission through normal mitochondrial energy metabolism, distribution and trafficking, and through synaptic calcium modulation. To date, there has been no extensive analysis of alterations in synaptic mitochondria associated with amyloid pathology in an amyloid β(Aβ)-rich milieu. Here, we identified differences in mitochondrial properties and function of synaptic vs. nonsynaptic mitochondrial populations in the trans-genic mouse brain, which overexpresses the human mutant form of amyloid precursor protein and Aβ. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of Aβ and mitochondrial alterations. The synaptic mitochondrial pool of Aβ was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular Aβ accumulation. Aβ-insulted synaptic mitochondria revealed early deficits in mitochondrial function, as shown by increased mitochondrial permeability transition, decline in both respiratory function and activity of cytochrome c oxidase, and increased mitochondrial oxidative stress. Furthermore, a low concentration of Aβ (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially Aβ-rich synaptic mitochondria, are more susceptible to Aβ-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.
机译：突触功能障碍和突触丧失是阿尔茨海默氏病（AD）的早期病理特征。突触是高能量需求和广泛的钙波动的场所。因此，突触传递需要高水平的ATP和恒定的钙波动。因此，突触线粒体对于通过正常的线粒体能量代谢，分布和运输以及通过突触钙调节来维持突触功能和传递至关重要。迄今为止，尚未对富含淀粉样蛋白（Aβ）的环境中与淀粉样蛋白病理相关的突触线粒体的变化进行广泛的分析。在这里，我们确定了转基因小鼠大脑中突触与非突触线粒体群体的线粒体特性和功能的差异，这种差异过表达了人类突变体形式的淀粉样蛋白和Aβ。与非突触线粒体相比，突触线粒体表现出更大程度的年龄依赖性Aβ积累和线粒体改变。早在非突触线粒体发作和大量细胞外Aβ积累之前，就检测到Aβ突触线粒体库的年龄仅为4 mo。 Aβ引起的突触线粒体显示线粒体功能的早期缺陷，如线粒体通透性增加，呼吸功能和细胞色素C氧化酶活性下降以及线粒体氧化应激增加所表明。此外，低浓度的Aβ（200 nM）会显着干扰线粒体的分布和轴突的运输。这些结果表明，突触线粒体，特别是富含Aβ的突触线粒体，更容易受到Aβ诱导的损伤，突显了与AD中突触变性有关的突触线粒体功能障碍的中心重要性。

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  • 作者

    Heng Du; Lan Guo; Shiqiang Yan; Alexander A. Sosunov; Guy M. McKhann; Shirley ShiDu Yan;

  • 作者单位

    Departments of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032;

    rnDepartments of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032;

    rnState Key Laboratory of Applied Organic Chemistry's Lanzhou University, Tianshui Southern Road 222, Lanzhou Gansu 730000, China;

    rnDepartments of Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032;

    rnDepartments of Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032;

    rnDepartments of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032 Departments of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 Departments of The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    synaptic AB; mitochondrial trafficking; mitochondrial oxidative stress mitochondrial dysfunction; synaptic injury;

    机译：突触AB线粒体运输;线粒体氧化应激线粒体功能障碍;突触损伤;

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