“阻断Aβ聚集/清除Aβ沉积”双功能Aβ疫苗在阿尔茨海默症免疫治疗中的作用机制研究

目前阿尔茨海默病（AD）的治愈遥遥无期，清除Aβ沉积的疫苗是AD新药研发的重点，但临床试验均宣布失败，原因在于疫苗的安全性弱及免疫原性差。课题组前期研发了一株在AD鼠中有强安全性、高免疫原性和能清除Aβ沉积的Aβ1-6疫苗。多数Aβ疫苗只能清除Aβ沉积，却不能从源头上阻断Aβ聚集。研究表明炎症相关蛋白ASC能够与Aβ结合并促进其聚集，然而Aβ与ASC的结合位点仍不明确，以其为靶点设计的Aβ疫苗能否抑制Aβ聚集并延缓AD病程尚无研究。本项目将确定Aβ42与ASC的作用位点，并以此Aβ表位为免疫原、诺如病毒P颗粒为载体设计Aβabs疫苗，在转基因鼠中考察其免疫原性，安全性和阻断聚集的能力。再与前期研发的Aβ1-6疫苗联用组成双功能AD疫苗，在转基因鼠中探究其免疫治疗效果和作用机制，期望同时诱导阻断Aβ聚集和清除Aβ沉积的抗体，实现对Aβ病理蛋白的彻底清除，为AD疫苗研发提供更明确的靶点和思路。

So far, no clinical drugs could cure AD, the vaccines focusing on reducing Aβ deposition are the main strategies in AD drug research. However, none of the AD immunotherapies has produced clinically meaningful results to date, mainly due to the weak safety and poor immunogenicity of the vaccine. In our preliminary study, we have developed a novel Aβ1-6 epitope vaccine, which is safe, highly immunogenic and could successfully reduce the Aβ deposition from the brain of APP/PS1 transgenic mice. The majority of the Aβ vaccines could only eliminate the deposited Aβ plaques, but not block the Aβ aggregation. Recently, it has been reported that microglia-derived ASC could bind rapidly to Aβ and increase the formation of Aβ oligomers and aggregates. However, the binding site on the Aβ42 with ASC has not been identified yet. Furthermore, the immunotherapeutic effect of the Aβ vaccine targeting this binding site remains unknown. In this study, we will first determine the interaction site between Aβ and ASC protein. Then we will develop a novel Aβabs epitope vaccine by inserting peptide containing this site into the loops of P particle and test whether it can block the Aβ aggregation and improve the cognitive decline in APP/PS1 transgenic mice. Afterwards, we will combine this Aβabs epitope with the prepared Aβ1-6 epitope vaccine together to form a dual-function Aβ vaccine. We will investigate the immunogenicity, safety, therapeutic effect and functional mechanisms of this combined AD vaccine in APP/PS1 transgenic mice. This novel dual-functional AD vaccine could efficiently block the aggregation of Aβ and clear the deposited Aβ at the same time, and entirely eliminate the pathological Aβ from the brain, which could provide more specific targets and ideas for the further AD vaccine development.