神经元轴突起始节异常在老年性痴呆症的发生发展中的作用

Axon initial segment (AIS) plays demonstrated roles in neuronal polarity, action potential initiation, neurodegenerative diseases and brain damage. There is evidence that a selective filter at the AIS that contributes to the selective penentration of membrane and cytosolic proteins in the distal area of the axon. Our preliminary results indicate that in the neurons from mice carrying presenilin-1 mutation, the selective filter at the AIS is damaged leading to mislocation of many proteins including NR2B. It has been accepted that AD is an age-related disease and AD is always associated with late stage of life. However, our data suggested that if carrying familial AD mutations (eg, PS1 mutations as examined in our study), neurons are abnormal from the very beginning (not until late stage of life) with development, protein trafficking, protein location, and AIS sub-cellular structure. Since AIS is associated with action potential generation and NR2B is high related to synaptic transmission, we think this may lead to many problems of mis-firing and synaptic transmission in these AD neurons, which may contribute to AD development and pathology.

神经元轴突起始节位于轴突前段，被证实在神经元极性形成、动作电位起始过程以及脑疾病、损伤等过程中发挥重要的作用。轴突起始节位置存在选择过滤装置可以特异性的通透细胞膜和胞浆内的蛋白，从而造成这些蛋白在胞体、树突、轴突中的特异性定位。我们的前期研究发现，携带presenilin-1突变的家族型老年性痴呆症动物神经元的轴突起始节处的选择过滤装置发生异常，造成了包括谷氨酸受体亚基NR2B等蛋白的错误定位。我们的结果提示，虽然家族型老年性痴呆症的病理学特征出现在老年阶段，但在神经元发育的早期就已经出现异常。在本项目中，我们将深入研究造成这种选择过滤装置异常的机制，确定选择过滤装置异常导致的神经元中蛋白定位，轴突运输，突触传导以及冲动发放的异常，并探讨轴突起始节异常在造成老年性痴呆症的轴突病变和轴突转运异常中的作用。研究成果将对理解老年性痴呆症的发生发展提供理论依据并对该症的预防与治疗提供新的思路。

在本项目中，我们主要研究了阿尔茨海默病（Alzheimer's disease, AD）神经元中轴突起始节（axon initial segment, AIS）长度和位置改变是否影响轴突髓鞘化，探讨AD神经元中AIS的损伤是否影响轴突物质转运，AIS的可塑性变化对于动作电位的产生和传播速度的影响及其分子机制，AD神经元中AIS结构改变是否影响突触的功能，是否可能通过影响轴突的伸长和导向或者影响原始纤毛的信号功能发挥作用，并研究了AIS的可塑性变化对长时程增强的影响。本课题发现了在家族型老年性痴呆突变的携带个体中，神经元在细胞发育早期就广泛存在轴突发育，细胞间交流，蛋白亚细胞器定位和功能等障碍，修正了过去以来一直认为的老年性痴呆是老年疾病，其病因出现在老年期的观点。这一发现对了解老年性痴呆，特别是家族型致病基因导致的痴呆提供了新的思路。