阿尔茨海默病小鼠模型成年早期过度髓鞘化的分子机制研究

Myelination contributes to nerve impulse conduction and the whole neural functions. Previous reports suggest that myelination abnormity might be one of the early pathological features of Alzheimer’s disease (AD). Our prophase work shows hypermyelination in early APP/PS1 mice, and suggests that Ankyrin G (AnkG) might contribute to Neuregulin 1 (Nrg1) related myelination through DR6 and Caspase 6 regulated pathway, but the exact mechanism is not clear. Using cellular and molecular biological and electrophysiological methods, our project will firstly reveal the interaction of AnkG and DR6 molecules, secondly investigate how DR6 recruits and activates Caspase6, and finally focus on the mechanism of how the expression level of Nrg1 is regulated by Caspase 6. Through this project, the expected results will help to clarify the mechanism of hypermyelination in APP/PS1 transgenic mice caused by down regulation of AnkG and following upregulation of Nrg1, which will also provide the theoretical basis for early AD brain myelin lesions.

髓鞘化异常影响神经冲动的传导进而对轴突和神经元的整体功能造成损伤，既往报道提示髓鞘化异常可能是阿尔兹海默病 (AD) 的早期病理特征之一。本课题组前期工作发现APP/PS1转基因小鼠模型成年早期阶段存在过度髓鞘化现象，并提示锚定蛋白Ankyrin G (AnkG) 可能通过肿瘤坏死因子受体6 (DR6) 和Caspase 6信号通路参与Neuregulin 1 (Nrg1) 介导的髓鞘化过程，但其确切机制尚不清楚。本项目将在课题组前期工作基础上，以APP/PS1转基因小鼠为模型，采用细胞分子生物学和电生理学等方法，首先揭示AnkG与DR6分子间相互作用，其次探讨DR6如何招募Caspase 6并使其处于激活状态，最后研究Caspase 6调控Nrg1表达的机制。本项目预期结果有助于阐明因AnkG含量下降所致APP/PS1转基因小鼠模型过度髓鞘化的分子机理，为AD脑早期髓鞘病变提供理论依据。