阿尔兹海默病（AD）与外周免疫抑制和脑内免疫细胞功能紊乱密切相关，其病理特征是Aβ和Tau蛋白沉积。我们已证实：4次接种流感疫苗（IV）打破免疫抑制，改善AD脑病理和认知缺陷。研究表明：PD-1抗体可抑制负性免疫调节，呈疗程依赖性减轻AD脑病理。那么，2次接种IV联合低剂量PD-1抗体是否减轻AD病理并改善认知功能呢，机制是什么？预实验发现，IV联合PD-1抗体上调脉络丛IFN-γ表达，促进外周单核-巨噬细胞PMDM入脑，增强小胶质细胞吞噬Aβ蛋白，改善AD小鼠认知缺陷。我们假设：联合免疫治疗募集PMDM入脑，调节小胶质细胞表达CD11c，缓解Aβ和Tau病理。本项目拟采用条件性敲除鼠、骨髓嵌合等工具，证实联合免疫治疗改善AD认知缺陷，阐明小胶质特异性IFN-γ/IFN-γR1/p38MAPK在免疫调节减轻AD病理中的关键机制，为寻找免疫调节联合阻断免疫检查点的AD治疗提供更充分的科学论据

Alzheimer’s disease is closely associated with peripheral immune inhibition and dysfunction of immune cells in the brain, characterized by Aβ burden and tau protein phosphorylation. We have confirmed that influenza vaccination (IV) for 4 times break through immunesupression and improve AD brain pathology and cognitive deficits. It has been reported that PD-1 antibodies (PD-1) inhibit negative immune regulation, followed by alleviating AD pathology in dose-dependent. Then, could IV for 2 times combined with low-dose of PD-1 antibody reduce AD pathology and improve cognitive function, what is the underlying mechanism? Data from our pilot tests have revealed that combined with IV and PD-1 increase the level of IFN-γ in choroid plexus, recruit peripheral monocyte-derived macrophages to the brain, enhance the ability to phagocytose Aβ protein by microglia, and improves cognitive deficits in AD mouse model. Therefore, we assume that combined treatment of IV and PD-1 recruit PMDM to the brain for the mitigation of AD pathology and the promotion of cognitive function, through regulating microglia expressing CD11c. In this project, the tools, such as conditional knockout mice, bone marrow chimeric mouse will be applied to reveal that microglia-specific IFN-γ/IFN-γR1/p38MAPK signaling play a vital role in the reduction of pathology in the combined immunotherapy for AD. This project will lay a solid foundation for future clinical application of immune-regulation synergized with immune checkpoint blockade.