Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18670-5. doi: 10.1073/pnas.1006586107. Epub 2010 Oct 11.
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 transgenic 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.
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，突触线粒体对于维持突触功能和传递至关重要，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。迄今为止，尚未广泛分析淀粉样蛋白病理学相关的突触线粒体改变在富含淀粉样蛋白 β（Aβ）的环境中。在这里，我们在过表达人突变形式的淀粉样前体蛋白和 Aβ 的转基因小鼠大脑中鉴定了突触和非突触线粒体群体之间线粒体特性和功能的差异。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。在 4 个月大的年龄，即在非突触线粒体和广泛的细胞外 Aβ积累之前，就已经检测到突触线粒体中的 Aβ 积累。Aβ 损伤的突触线粒体显示线粒体功能早期缺陷，表现为线粒体通透性转换增加、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。此外，低浓度的 Aβ（200 nM）显著干扰了轴突中线粒体的分布和运输。这些结果表明，突触线粒体，尤其是富含 Aβ 的突触线粒体，更容易受到 Aβ 诱导的损伤，突出了与 AD 中突触退化发展相关的突触线粒体功能障碍的核心重要性。
