视网膜多维检测对阿尔茨海默病的早期识别及其机制探索

阿尔茨海默病（Alzheimer’s disease, AD）临床诊断滞后于病理改变，极大限制疾病治疗的发展，其主要原因是缺乏便捷、精准、无创的早期诊断方法。视网膜是中枢神经系统的脑外延伸部分，可实现无创检测并精确至细胞水平，是潜在的AD早期诊断“窗口”。本课题聚焦于AD全病程的视网膜表现，以前瞻性、动态随访的研究设计，在前期已建立的“华山认知障碍队列”和“上海老龄队列”中，通过光学相干断层扫描，采集视网膜多维标志物数据（如：神经纤维层厚度、黄斑容积、微血管结构、视网膜β淀粉样蛋白沉积/磷酸化Tau聚集等），评价其反映疾病特征及临床进展的价值。同时，在5xFAD小鼠模型和体外培养各细胞系中，观测视网膜上述病变的空间分布及时间演变特征，以脑/眼共性改变为切入点，探索UPS-ALP两系统交互作用参与脑与视网膜蛋白清除的分子机制，寻求共性治疗新靶点。

Pathological changes accumulate in the brain over 15–20 years prior to the establishment of clinical diagnosis of Alzheimer’s disease (AD), the lack of a convenient in vivo biomarker stands as a lost opportunity for early intervention. The retina is a developmental extension of the brain and is the only part of the central nervous system that can be imaged non-invasively at sub-cellular resolutions. Thus, the retinal imaging may serve as a “window” to monitor brain pathology in AD. This study aims to evaluate multi-modal retina imaging, based on optical coherence tomography (OCT), in the early diagnosis and monitoring of AD, in two well-established hospital- and community-based cohorts. Comparisons among various retinal indexes (including retinal nerve fiber thickness, micro-vasculature, Abeta and Tau accumulation) and between the retinal and traditional biomarkers will be performed. Meanwhile, 5xFAD transgenic mice and in vitro RGC cell culture system will be used to investigate the over-time retinal pathological changes and the spatial distribution features. Experimental study will be focused on the molecular mechanism of the interplay between ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP), and its role in the pathogenesis of AD. This study holds promise for the establishment of ocular marker for AD, and ultimately for the development of disease-modifying intervention.