Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
Department of Neurology, Fujian Institute of Geriatrics, the Affiliated Union Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Brain Res Bull. 2018 Mar;137:285-293. doi: 10.1016/j.brainresbull.2017.12.013. Epub 2017 Dec 28.
Previous studies have demonstrated myelin deficits in Alzheimer's disease (AD). However, it is still unclear whether myelin deficits occur at early stage of AD. Our study aimed to investigate myelin deficits in 5XFAD mice dynamically in different cognition-associated brain regions at early stage of AD. Transmission electron microscopy (TEM) was applied to detect myelin changes in late-myelinating regions such as prelimbic area (PrL), retrosplenial granular cortex (Rsg), field CA1 of hippocampus (CA1) and entorhinal cortex (ERC) respectively at different stages (1, 2, 3 and 5 months of age) in 5XFAD mouse model. In addition, we assessed spatial learning and memory with Morris water maze (MWM) in 5XFAD mice. Myelin deficits in 5XFAD mice started from 1 month of age and this deterioration continued during ageing, whereas the same myelin abnormality could only be observed in 5-month-old wild-type mice. Additionally, the g-ratio (an index associated with myelin thickness) was increased in 1-month-old 5XFAD mice in the regions including PrL, CA1 and ERC, compared to wild-type mice. As animals aged, the increased g-ratio in 5XFAD appeared in more regions of the brain. Moreover, 5XFAD mice showed spatial memory deficits from 1 month of age and spatial learning deficits from 2 months of age. In conclusion, myelin deficits occurred at an early stage and progressed with ageing in 5XFAD mouse model. Notably, a sequential myelin change was detected in cognition-associated brain regions. Combined with cognitive examinations, this study suggests that myelin changes might contribute to cognitive dysfunction.
先前的研究表明阿尔茨海默病（AD）存在髓鞘缺陷。然而，AD 的早期阶段是否存在髓鞘缺陷仍不清楚。我们的研究旨在动态研究 AD 早期 5XFAD 小鼠不同认知相关脑区的髓鞘缺陷。应用透射电子显微镜（TEM）分别检测晚期髓鞘形成区域（如前额叶皮层（PrL）、后顶叶颗粒皮层（Rsg）、海马 CA1 区和内嗅皮层（ERC））在 5XFAD 小鼠模型不同阶段（1、2、3 和 5 个月龄）的髓鞘变化。此外，我们在 5XFAD 小鼠中使用 Morris 水迷宫（MWM）评估空间学习和记忆。5XFAD 小鼠的髓鞘缺陷始于 1 月龄，这种恶化在衰老过程中持续存在，而相同的髓鞘异常仅在 5 月龄野生型小鼠中观察到。此外，与野生型小鼠相比，1 月龄 5XFAD 小鼠的 PrL、CA1 和 ERC 等区域的 g-ratio（与髓鞘厚度相关的指标）增加。随着动物年龄的增长，5XFAD 中 g-ratio 的增加出现在大脑的更多区域。此外，5XFAD 小鼠从 1 月龄开始表现出空间记忆缺陷，从 2 月龄开始表现出空间学习缺陷。总之，髓鞘缺陷在 5XFAD 小鼠模型中早期发生，并随着年龄的增长而进展。值得注意的是，在认知相关脑区检测到顺序性髓鞘变化。结合认知检查，本研究表明髓鞘变化可能导致认知功能障碍。
