Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model
Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model
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DOI：
10.1073/pnas.1006586107
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发表时间：
2010-10-26
影响因子：
11.1
通讯作者：
Yan, Shirley ShiDu
中科院分区：
文献类型：
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作者：
Du, Heng;Guo, Lan;Yan, Shirley ShiDu
突触功能障碍和突触丧失是阿尔茨海默病（AD）的早期病理特征。突触是高能量需求和广泛钙波动的部位；因此，突触传递需要高水平的ATP和持续的钙波动。因此，突触线粒体通过正常的线粒体能量代谢、分布和运输以及突触钙调节，对维持突触功能和传递至关重要。迄今为止，还没有广泛的分析突触线粒体的改变与淀粉样蛋白病理在淀粉样蛋白丰富的环境（A β）。在这里，我们发现了转基因小鼠大脑中突触与非突触线粒体种群的线粒体特性和功能的差异，转基因小鼠大脑过度表达人类淀粉样蛋白前体蛋白和A β的突变形式。与非突触线粒体相比，突触线粒体显示出更大程度的年龄依赖性a β积累和线粒体改变。突触线粒体A β库在4个月大的时候就被检测到，远远早于非突触线粒体和广泛的细胞外A β积累的开始。β -损伤的突触线粒体显示出线粒体功能的早期缺陷，表现为线粒体通透性转变增加，呼吸功能和细胞色素c氧化酶活性下降，线粒体氧化应激增加。此外，低浓度a β (200 nM)显著干扰线粒体分布和轴突运输。这些结果表明突触线粒体，特别是富含A - β的突触线粒体，更容易受到A - β诱导的损伤，突出了突触线粒体功能障碍与AD突触变性发展相关的核心重要性。
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 beta (A beta)-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 A beta. Compared with nonsynaptic mitochondria, synaptic mitochondria showed a greater degree of age-dependent accumulation of A beta and mitochondrial alterations. The synaptic mitochondrial pool of A beta was detected at an age as young as 4 mo, well before the onset of nonsynaptic mitochondrial and extensive extracellular A beta accumulation. A beta-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 A beta (200 nM) significantly interfered with mitochondrial distribution and trafficking in axons. These results demonstrate that synaptic mitochondria, especially A beta-rich synaptic mitochondria, are more susceptible to A beta-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction relevant to the development of synaptic degeneration in AD.