衰老中自身抗体的变化特点及其在阿尔茨海默病发生中的作用和机制研究

Aging is the most important risk factor for Alzheimer’s disease (AD), however, the mechanisms underlying the development of AD during aging remain largely unknown. Immune aging leads to lowered immunity and abnormal autoimmune responses. Immunity has been realized to play critical roles in the pathogenesis of AD. Brain-reactive autoantibodies are nearly ubiquitous in human blood, but their pathophysiological significance remains largely unclear. We found that autoantibody profiles become disordered in AD patients from Chongqing Aging Study, and this disorder was further confirmed in AD cohort from Australian Imaging, Biomarker and Lifestyle flagship Study of Aging (AIBL); and the levels of autoantibodies to amyloid-beta (Abeta) was closed associated with the cognitive function, brain Abeta deposition and CSF Abeta42/pTau levels at baseline; and importantly we found that autoantibodies to Abeta regulate Abeta metabolism. Based on these preliminary and critical findings, we propose that disorder of autoantibody profiles during aging participates in the development of AD during aging; and autoantibody profiles might be potential biomarkers and therapeutic targets for AD. Therefore, we plan to conduct longitudinal prospective study to investigate the natural trajectory of autoantibody profiles during aging, and identify the AD related autoantibodies; Next we will characterize the biological functions of these AD related autoantibodies and their roles in AD pathogenesis; Then we will explore the potential of autoantibody profiles to be biomarkers for early diagnosis of AD, and investigate the therapeutic effects of protective autoantibodies against AD. This proposed study will help us to reveal the immune mechanisms underlying the development of AD during AD, and develop autoantibody based diagnosis and therapies for AD.

衰老是阿尔茨海默病（AD）最为重要的危险因素，衰老演变为AD的具体机制亟待阐明。免疫衰老导致免疫力降低和异常自身免疫。近年发现免疫功能与AD关系密切。人体广泛存在针对自身抗原的自身抗体，其病理生理意义不清。我们在重庆队列和澳大利亚AIBL队列中发现，AD患者自身抗体谱紊乱；其中抗Aβ自身抗体与AD基线认知功能、脑内Aβ和pTau水平显著相关，并参与Aβ代谢调控。我们提出假说：衰老过程中自身体液免疫紊乱参与衰老向AD的演变；自身抗体具有AD诊断和防治潜力。本项目通过前瞻性队列和实验研究，探讨衰老过程中自身抗体谱的变化特点和规律，筛选和鉴定AD相关自身抗体；在此基础上探讨AD相关自身抗体的功能，及其在AD发生中的作用和机制；并寻找具有AD早期诊断价值的自身抗体标志物，探讨保护性自身抗体对AD的干预作用。本项目有望揭示衰老演变为AD的免疫新机制，为AD早期诊断和防治提供新方法和新策略。

衰老是阿尔茨海默病（AD）最为重要的危险因素，衰老演变为AD的具体机制亟待阐明。免疫衰老导致免疫力降低和异常自身免疫。近年来发现免疫功能与AD关系密切。本项目通过前瞻性队列和实验研究，探讨衰老过程自身抗体在AD发生中的作用和机制，并寻找具有AD早期诊断价值的自身抗体标志物，探讨保护性自身抗体对AD的干预作用。在本项目资助完成预定研究目标，取得如下成果：1. 在重庆老化研究队列人群和AIBL队列人群中发现衰老和AD发生过程中自身抗体谱的变化特征，其中包含多个AD病理环路重要蛋白的自身抗体，如Aβ自身抗体和BACE1自身抗体；2. 阐明自身抗体在衰老向AD演变过程中的作用和机制，揭示Aβ自身抗体表位相关的功能异质性；3. 自身抗体对衰老向AD演变的早期诊断价值，其中，Aβ自身抗体和BACE1自身抗体能够预测AD病程变化特征；4. 从AD患者变化的自身抗体中筛选出Bim自身抗体，发现其具有AD保护作用，提示针对Bim的免疫治疗可能成为一种针对神经元凋亡的AD潜在治疗策略；5. 从系统角度探讨AD的发生机制和防治方法，发现肾脏等外周脏器组织具有AD病理物质清除能力，外周系统疾病促进AD发生发展。本项目有望揭示衰老演变为AD的免疫新机制，为AD早期诊断和防治提供新方法和新策略。.上述研究的部分成果，已在Science Advances、Lancet Infectious Diseases、Molecular Psychiatry、Acta Neuropathologica等国际专业期刊发表研究论文10篇，获得中国和国际发明专利3项，完成了任务书中的考核指标。培养国家优青1名，重庆市 “巴渝学者”和“英才计划”青年拔尖人才各1名，博士后1名，博士13名，硕士7名，全军优博2名，重庆市优博3名。

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