Stahon Katharine E, Bastian Chinthasagar, Griffith Shelby, Kidd Grahame J, Brunet Sylvain, Baltan Selva
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, Ohio 44195
J Neurosci. 2016 Sep 28;36(39):9990-10001. doi: 10.1523/JNEUROSCI.1316-16.2016.
The impact of aging on CNS white matter (WM) is of general interest because the global effects of aging on myelinated nerve fibers are more complex and profound than those in cortical gray matter. It is important to distinguish between axonal changes created by normal aging and those caused by neurodegenerative diseases, including multiple sclerosis, stroke, glaucoma, Alzheimer's disease, and traumatic brain injury. Using three-dimensional electron microscopy, we show that in mouse optic nerve, which is a pure and fully myelinated WM tract, aging axons are larger, have thicker myelin, and are characterized by longer and thicker mitochondria, which are associated with altered levels of mitochondrial shaping proteins. These structural alterations in aging mitochondria correlate with lower ATP levels and increased generation of nitric oxide, protein nitration, and lipid peroxidation. Moreover, mitochondria-smooth endoplasmic reticulum interactions are compromised due to decreased associations and decreased levels of calnexin and calreticulin, suggesting a disruption in Ca(2+) homeostasis and defective unfolded protein responses in aging axons. Despite these age-related modifications, axon function is sustained in aging WM, which suggests that age-dependent changes do not lead to irreversible functional decline under normal conditions, as is observed in neurodegenerative diseases.
Aging is a common risk factor for a number of neurodegenerative diseases, including stroke. Mitochondrial dysfunction and oxidative damage with age are hypothesized to increase risk for stroke. We compared axon-myelin-node-mitochondrion-smooth endoplasmic reticulum (SER) interactions in white matter obtained at 1 and 12 months. We show that aging axons have enlarged volume, thicker myelin, and elongated and thicker mitochondria. Furthermore, there are reduced SER connections to mitochondria that correlate with lower calnexin and calreticulin levels. Despite a prominent decrease in number, elongated aging mitochondria produce excessive stress markers with reduced ATP production. Because axons maintain function under these conditions, our study suggests that it is important to understand the process of normal brain aging to identify neurodegenerative changes.
衰老对中枢神经系统白质（WM）的影响备受关注，因为衰老对有髓神经纤维的整体影响比对皮质灰质的影响更为复杂和深刻。区分正常衰老引起的轴突变化与神经退行性疾病（包括多发性硬化症、中风、青光眼、阿尔茨海默病和创伤性脑损伤）引起的轴突变化很重要。利用三维电子显微镜，我们发现，在小鼠视神经（这是一条纯净且完全有髓鞘的白质束）中，衰老的轴突更大，髓鞘更厚，其特征是线粒体更长更厚，这与线粒体塑形蛋白水平的改变有关。衰老线粒体的这些结构改变与较低的ATP水平以及一氧化氮生成增加、蛋白质硝化和脂质过氧化有关。此外，由于钙连接蛋白和钙网蛋白的结合减少及水平降低，线粒体 - 滑面内质网相互作用受损，这表明衰老轴突中Ca(2+) 稳态受到破坏且未折叠蛋白反应存在缺陷。尽管存在这些与年龄相关的改变，但衰老白质中的轴突功能仍得以维持，这表明在正常情况下，年龄依赖性变化不会导致不可逆转的功能衰退，这与神经退行性疾病中观察到的情况不同。
衰老 是包括中风在内的多种神经退行性疾病的常见风险因素。随着年龄增长，线粒体功能障碍和氧化损伤被认为会增加中风风险。我们比较了1个月和12个月时获得的白质中轴突 - 髓鞘 - 结 - 线粒体 - 滑面内质网（SER）的相互作用。我们发现，衰老的轴突体积增大、髓鞘更厚、线粒体更长更厚。此外，SER与线粒体的连接减少，这与钙连接蛋白和钙网蛋白水平降低相关。尽管数量显著减少，但延长的衰老线粒体产生过多的应激标志物，同时ATP生成减少。由于轴突在这些条件下维持功能，我们的研究表明，了解正常脑衰老过程对于识别神经退行性变化很重要。
