GDP解离抑制因子2在阿尔茨海默病中促进Aβ聚集的功能和机制研究

遗传和生物标志物研究均支持β淀粉样肽（Aβ）是阿尔茨海默病（AD）的始动因素。可溶性Aβ寡聚体是AD相关淀粉样蛋白的主要致病形式，但是促进Aβ寡聚体形成的作用机制鲜有报道。我们前期研究发现GDP解离抑制因子2（GDI2）存在于AD病人和AD模型小鼠脑淀粉样斑块中，GDI2能够与Aβ直接结合并加速Aβ寡聚体的形成。我们据此提出假说：GDI2通过与Aβ单体直接结合，改变Aβ构象，加速Aβ寡聚体的形成，从而增强Aβ寡聚体介导的神经毒性，加重AD认知功能损害。本项目拟通过体内和体外实验研究GDI2对Aβ寡聚体形成、神经毒性作用、AD样病理和认知行为的影响；并进一步研究GDI2促进Aβ寡聚体形成的作用机制。我们有望确定一种在Aβ寡聚体形成中起重要作用的蛋白，丰富我们对Aβ寡聚体形成机制的认识，并为靶向GDI2减少Aβ寡聚体形成的治疗策略提供理论基础。

The central and early role of β-amyloid peptide (Aβ) in Alzheimer's Disease (AD) pathogenesis has been confirmed by genetic and biomarker studies in AD. Soluble Aβ oligomers are pathogenic forms of AD associated amyloid. However, the mechanisms underlying the formation of Aβ oligomers are rarely reported. Our study found that GDP dissociation inhibitor 2 (GDI2) exists in the amyloid plaques of brain tissues from the AD patients and the AD mice models. Our study also found that GDI2 could directly interact with Aβ and accelerate the formation of Aβ oligomers. Thus, we propose the hypothesis that GDI2 directly interacts with Aβ monomers via specific binding domain, accelerating the formation of Aβ oligomers by changing the conformation of Aβ, and thus enhances Aβ oligomer-mediated neurotoxicity and aggravates the cognitive impairment of AD. In this project, we will investigate the effects of GDI2 on Aβ oligomer formation, neurotoxicity, AD-like pathology and cognitive behavior in vitro and in vivo. Furthermore, we will study the mechanism of GDI2-promoted Aβ oligomers formation. This project will identify the pathophysiological role of GDI2 in AD, and it will also clarify the mechanism of GDI2-promoted Aβ aggregation, providing a theoretical basis for the GDI2-based therapeutic strategy of Aβ aggregation-reducing.