抗p75NTR胞外段自身抗体在阿尔茨海默病中的作用和临床意义研究

The immunosenescence during aging can lead to abnormal autoimmune responses causing the over-production of autoantibodies against varieties of antigens in the brain, which have been realized to play critical roles in the pathogenesis of Alzheimer’s disease (AD). We previously found that the soluble extracellular domain of neurotrophin receptor p75NTR (p75ECD) can inhibit the aggregation of Aβ and block Aβ-induced neurotoxicity, which is considered as an important endogenous protective factor for AD. However, the shedding of p75ECD is impaired in AD, with the mechanism largely unknown. We recently found that the neurons in AD brain were more frequently found to be bound with IgG autoantibodies. Besides, the level of anti-p75ECD autoantibody was elevated in the CSF of AD patients compared with normal controls, which was also negatively correlated with the CSF level of p75ECD. Based on these preliminary and important findings, we propose that the anti-p75ECD autoantibody may participate in the pathogenesis and development of AD by neutralizing the AD-protective effects of p75ECD, inhibiting its shedding, or activating the membrane attack complex which leads to neuronal death after binding to the surface of neurons expressing p75NTR. Therefore, we plan to conduct clinical and experimental study to investigate the natural trajectory of anti-p75ECD autoantibody profiles during aging and the transformation from normal ageing to AD, characterize the biological functions and roles of anti-p75ECD autoantibody in AD pathogenesis, and explore the potential of anti-p75ECD autoantibody to be biomarkers in the early diagnosis and prediction of AD. This project will help us to reveal the roles and clinical significance of anti-p75ECD autoantibody in AD, and to investigate novel mechanisms as well as novel early diagnosis strategies of AD from an autoimmune perspective.

衰老中伴随的免疫衰老可导致自身免疫异常而产生针对脑内各类抗原的自身抗体，与阿尔茨海默病（AD）的发生关系密切。我们前期研究发现神经营养因子受体p75NTR代谢释放的胞外段（p75ECD）具有神经保护作用；但AD患者脑内存在p75ECD释放障碍，机制不明。我们近期发现：AD脑内神经元上结合的自身抗体增多；AD脑内抗p75ECD自身抗体水平增加，且与p75ECD水平呈负相关。因此提出假说：抗p75ECD自身抗体可能通过中和p75ECD的AD保护作用、抑制p75ECD释放或形成膜攻击复合物而诱导神经元死亡的方式参与AD。本项目拟通过临床和实验研究，分析抗p75ECD自身抗体在衰老及其向AD演变中的变化特点，研究其在AD中的作用和具体机制，并探索抗p75ECD自身抗体对AD早期诊断和预测的价值。本项目对于从自身免疫角度阐明AD发病新机制和早期诊断新方法具有重要科学意义。

神经营养因子受体p75NTR经剪切后释放的胞外段（p75ECD）具有抑制Aβ产生、阻止Aβ聚集和拮抗Aβ神经毒性的作用，是一种内源性阿尔茨海默病（AD）保护性分子。既往研究表明AD患者脑内存在p75ECD释放障碍，但其代谢调控机制尚不清楚。本项目通过研究发现：1）AD患者体内抗p75ECD自身抗体（p75ECD-NAbs）水平显著高于对照组，且AD患者脑脊液中p75ECD-NAbs水平与p75ECD呈负相关，与认知功能评分（MMSE）、AD生物标志物（Aβ42）呈负相关，初步确定了p75ECD-NAbs在AD诊断中的价值和作用；2）对APP/PS1转基因小鼠分别采用腹腔注射p75ECD、p75ECD逆序列蛋白（Re-p75ECD）、免疫佐剂的方法构建了p75ECD主动免疫组（Tg-p75ECD组）、自身免疫对照组（Tg-Re组）和空白对照组（Tg-CFA组）的小鼠模型，发现Tg-p75ECD组小鼠认知障碍及脑内AD病理改变显著加重，其主要机制很可能是升高的p75ECD-NAbs中和了脑内p75ECD，进而导致Aβ清除受阻；3）纳入AD患者366例、对照组人群390例，通过基因分型后发现p75NTR编码基因rs2072446位点显著增加了中国汉族人群的AD患病风险（OR=1.79）；同时，利用美国阿尔茨海默病神经影像学研究计划（Alzheimer's Disease Neuroimaging Initiative, ADNI）数据库中47例AD患者、469例轻度认知功能障碍（MCI）患者及276例正常对照者的数据，分析后发现在APOE ε4非携带者中，rs2072446多态性位点增加了脑内Aβ沉积及AD的进展风险。本项目的完成阐明了p75ECD-NAbs和rs2072446位点均可导致AD患者脑内的p75ECD释放障碍，进而参与AD，从自身免疫和遗传学的角度发掘了促使AD发生发展的新机制，为AD的早期诊断和潜在干预靶点提供了新思路。