本课题依据我们在阿尔茨海默病(AD)发病机制研究中获得的最新成果，研究和发现早期诊断AD的新型体液生物标志物。β淀粉样肽(Aβ)是AD发病的核心病理机制，我们最近发现脑组织内的天冬酰胺内肽酶(AEP)是Aβ生成级联的上游信号，AEP同时介导了Aβ生成增多和tau蛋白病变，AEP对淀粉样前体蛋白（APP）和tau的剪切加工是AD发病的早期事件；并且，AEP在年龄依赖性的AD发病中起关键作用。所以我们提出：1）AEP相关病变分子是反映AD早期病变的生物标志物； 2）AEP是早期干预AD的新靶点。为验证此科学假说，本课题应用质谱蛋白质组学技术检测血浆和脑脊液中AEP生成物的变化，研究和确定它们对早期AD的诊断效力，以及AEP的药物靶点作用。研究对象包括轻度认知损害（MCI）者、痴呆期AD患者和AD动物模型，目标是建立全新的体液（脑脊液或血浆）生化检测指标，用于AD的早期诊断和疾病干预。

This project was designed to identify novel body fluid biomarker for Alzheimer’s disease (AD) based on our most recent discovery in the pathological mechanism of AD. The β-Amyloid peptides (Aβ) is believed to be the key mediator of AD pathology. We recently found that Asparagine Endopeptidase (AEP) is progressively unregulated and activated during ageing in the mouse brain. Moreover, AEP is also elevated and activated in human AD brains compared to normal controls. The active AEP cleaves both amyloid precursor protein (APP) and tau, two major pathogenic players in AD. Processing of APP by AEP facilitates BACE1 to cleave APP, leading to β-amyloid upregulation. On the other hand, active AEP cleaves tau, abolishes its microtubule assembly function, induces tau aggregation, and triggers neurodegeneration. We will test the hypothesis that concentration and activity of AEP, the APP and tau fragments in the cerebrospinal fluid (CSF) and blood can serve as biomarkers for the early diagnosis of Alzheimer's disease. The mass spectrometry-based proteomics will be used to measure biomarker level in the CSF and blood that were obtained from mild cognitive impairment (MCI) and AD patients, as well as AD animal models. Implement of this project in Shanghai Jiao Tong University School of Medicine will open a new avenue for the prediction and prevention of future onset of AD.