Peking University, Shenzhen Graduate School, School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Shenzhen, China.
Peking University, Shenzhen Graduate School, School of Chemical Biology and Biotechnology, State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Shenzhen, China.
Neurobiol Aging. 2020 Dec;96:223-232. doi: 10.1016/j.neurobiolaging.2020.09.011. Epub 2020 Sep 12.
One major pathological process in Alzheimer's disease is mediated by hyperphosphorylated tau, which includes altered microtubules (MTs) and functions associated with tau. A potential way to compensate for altered MT function is to use an MT stabilizer, such as epothilone D (EpoD). Previous studies have demonstrated improved cognitive functions and axonal transport by EpoD in tau-mutation mice. Here, we demonstrated that extended EpoD treatment also has beneficial effects on APP/PS1 double-transgenic mice, improving their motor and spatial memory, increasing key synaptic protein levels, while not affecting amyloid plaque density or level of tau phosphorylation. Interestingly, EpoD appears to improve the retrieval of formed memories. We also observed improved axonal transport of mitochondria in cultured neurons from APP/PS1 mice. In addition, higher level of perineuronal nets are found in APP/PS1 mice injected with EpoD, suggesting potential contributions of increased inhibition. Our results suggest potential therapeutic value of EpoD in treating Alzheimer's disease.
阿尔茨海默病的一个主要病理过程是由过度磷酸化的 tau 介导的，其中包括微管（MTs）的改变和与 tau 相关的功能。一种潜在的补偿 MT 功能改变的方法是使用 MT 稳定剂，如埃坡霉素 D（EpoD）。以前的研究表明，EpoD 可改善 tau 突变小鼠的认知功能和轴突运输。在这里，我们证明了延长 EpoD 治疗对 APP/PS1 双转基因小鼠也有有益的影响，改善了它们的运动和空间记忆，增加了关键突触蛋白的水平，而不影响淀粉样斑块密度或 tau 磷酸化水平。有趣的是，EpoD 似乎改善了已形成记忆的检索。我们还观察到培养的 APP/PS1 小鼠神经元中线粒体的轴突运输得到改善。此外，在注射 EpoD 的 APP/PS1 小鼠中发现了更高水平的神经周细胞网络，表明增加抑制作用的潜在贡献。我们的结果表明 EpoD 在治疗阿尔茨海默病方面具有潜在的治疗价值。
