EphrinB3胞内信号介导的早期阿尔茨海默病发病机制的研究

The decrease of mature synapses and synaptic plasticity is a typical pathology in the early stages of Alzheimer's disease (AD) that may be associated with a down-regulation of ephrinB expression, a protein highly expressed in hippocampus. EphrinB3 is capable of transducing bidirectional signaling, being a single transmembrane protein, to promote neurogenesis and circuit formation, and regulate neural dendrite development and spine maturation. Moreover, ephrinB intracellular segment can be cleaved from cell membrane by γ-secretase, a key proteinase for the development of AD, which results in an accumulation of C-terminal fragment in the nuclei. Our proposed studies focus on how the pathogenesis in the early stage of AD is modulated by intracellular signaling of ephrinB3. We aim to clarify how γ-secretase cleaves ephrinB3 and what role of ephrinB intracellular domain on AD pathogenesis, and to identify the intracellular signal pathway of ephrinB3 and related downstream molecules by using transgenic AD animal model and ephrinB3 mutant mice. Our studies may lead to an increased understanding of the pathogenesis of AD and novel potential therapeutic targets for treatment of AD or ageing related memory decline.

在阿尔茨海默病早期，成熟神经突触减少，突触可塑性减退，神经功能受到损害。这种退行性病变可能与其海马特异性高表达蛋白ephrinB的表达量下调相关。EphrinB3作为一种单跨膜蛋白，在神经细胞上传递双向信号，促使神经发生和神经环路的形成，控制神经元的树突发育和树突棘成熟。EphrinB从细胞膜上的脱离依赖于与AD相关的蛋白水解酶γ-分泌酶的剪切，其被剪切的胞内蛋白片段在AD神经元核内含量上调。本项目围绕ephrinB3胞内信号在AD早期发病过程中作用机制这一核心问题，将利用AD小鼠模型以及eprinB3敲除和胞内端突变小鼠，研究γ-分泌酶对ephrinB3的剪切过程及其胞内端在AD病理过程中所发挥的作用，明确ephrinB3胞内端信号在AD神经元中的作用通路及相关分子调节机制。本研究将有助于深入理解AD的发病机制和发现治疗AD及老年记忆减退的新靶点。

在阿尔茨海默病早期，成熟神经突触减少，突触可塑性减退，神经功能受到损害。这种退行性病变可能与其海马特异性高表达蛋白ephrinB的表达量下调相关。EphrinB3作为一种单跨膜蛋白，在神经细胞上传递双向信号，促使神经发生和神经环路的形成，控制神经元的树突发育和树突棘成熟。EphrinB从细胞膜上的脱离依赖于与AD相关的蛋白水解酶γ-分泌酶的剪切，其被剪切的胞内蛋白片段在神经元细胞核内的稳定性不同野生型，参与调节神经元的功能和形态。海马区CA1和DG区的ephrinB3具有高表达，可以调控小鼠的社交能力和旷场活动能力。我们这一发现阐明ephrinB3及其胞内端在阿尔茨海默病的神经细胞内的主要功能和调节机制，为临床上治疗阿尔茨海默病的提供新的思路。