应用蛋白酶荧光成像技术研发新的AD早期生物标志物

Alzheimer’s disease (AD) results mainly from brain aging and neural degeneration. An important and critical task in basic and clinical AD research is to find new biomarkers for the diagnosis of early-onset of dementia. The metabolism cascade from amyloid precursor protein (APP) to Aβ is the key pathological change underlying AD progression. More recently, a lysosomal asparagine endopeptidase (AEP), was found simultaneously cleaves APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). Therefore, we propose to develop the protease AEP into a new AD biomarker. However, AEP is primarily located in cellular lysosome; it is not feasible to measure the level fluctuations of brain-derived AEP in the body fluid. The technique of fluorescent nanoprobe-based imaging has shown great potential in disease diagnosis and therapy, therefore we plan to use an AEP-responsive fluorescent nanoprobe and in vivo imaging method to verify our hypothesis. The objects of this study are well-established model mice that simulate brain aging and AD. In this animal study, we will correlate the value of functional AEP imaging with process of brain aging and degenerating. The specific aim is to validate that AEP imaging is able to predict AD, thus providing new idea for early detection/screening of AD.

阿尔茨海默病(AD)是脑衰老和退行性变的结果，探寻新的生物标志物是一直AD研究的重要任务。淀粉样前体蛋白（APP）异常代谢是AD发病的关键机制，我们新近发现天冬酰胺内肽酶(AEP)是一个新的APP代谢酶，它在β和γ分泌酶之前对APP进行预加工，能促进β淀粉样蛋白的生成。AEP处于APP代谢途径的上游，脑内AEP的激活是AD发病的早期事件，由此我们设想把蛋白酶AEP开发为新的AD生物标志物。AEP主要定位于细胞内溶酶体，在活体状态下宜用生物成像的手段将其显现。本课题拟采用AEP响应的荧光纳米探针和非侵入式定量分子影像技术，研究AEP的活性变化与脑衰老和退行性演变的关系，研究对象为模拟大脑衰老和AD病变的实验动物，目标是证明脑内AEP功能成像可以预测AD，为早期识别AD及其发病预警提供新思路。

阿尔茨海默病(AD)缺乏简便、实用和有效的早期生物标志物，是AD研究中亟待突破的难题。我们在这个研究方向上发现脑内的天冬酰胺内肽酶(AEP)是AD发病的早期事件，AEP的上调和激活表征了AD病变的早期阶段。由于AEP位于细胞内的溶酶体，它进入体液的浓度与脑内的水平不成比例，很难用体液生物标志物的方法测定脑内AEP的活性。所以，本项目采用AEP响应的荧光纳米探针和非侵入式定量分子影像技术，研究AEP的活性变化与脑衰老和退行性演变的关系，研究对象为模拟大脑衰老和AD病变的实验动物。取得的关键成果是，AD模型小鼠大脑的AEP活体成像分析能够如实反映AD的早期病变，AEP功能成像有潜力成为一种新型的AD生物标志物，在这个方向上继续开展转化医学研究，将来可以为早期识别AD及其发病预警提供新的评价依据。