β淀粉样蛋白在年龄相关性白内障发病中的作用及其机制研究

The blindness prevention project of China in the 21st century focuses on the prevention and treatment for cataract, thus the pathogenesis and non-surgical intervention of age-related cataract (ARC) has become a hotspot. Based on a variety of evidence, recently researchers pointed out the possibility of ARC belonging to amyloidosis disease, which is characterized by pathological accumulation of Aβ protein leading to severe oxidative stress. Studies in vitro found that Aβ induced lens opaque with mophologic and cytologic changes similar to ARC, at the same time the relations between Aβ and ARC in vivo have not been reported. Our previous study discovered the upregulation of Aβ in lens epithelial cells of ARC patiens compared to the normal subjects of the same age. The current study is to further investigate in vivo: 1. the changes of Aβ level during the onset of ARC of human and animal model (rats under ultraviolet irradiation). 2. If cataract could be induced in rats by intracameral injection of Aβ, and its machanism. 3. If intracameral injection of SIRT1 activator，which was proved to inhibit Aβ generation, could prevent cataract formation in rats. This study will further discover the the effect of Aβ on the pathogenesis of ARC in vivo and its machanism, and lay a foundation for the non-surgical treatment and prevention for ARC.

白内障是我国21世纪防盲治盲工作重点，年龄相关性白内障（ARC）的发病机制和非手术干预已成为研究热点。近来研究者在多种证据支持下提出ARC属于淀粉样疾病。淀粉样疾病发生的中心环节为β淀粉样蛋白（Aβ）的累积及其氧化损伤作用。研究已发现Aβ在体外可诱导晶状体混浊，且其形态特点和细胞学改变近似于ARC。但尚无文献报道在体内环境下Aβ与ARC的相关性。我们初步研究发现，ARC患者晶状体上皮细胞中的Aβ含量明显高于同年龄正常晶状体。本课题拟进一步研究：1.在人ARC发生中及大鼠紫外线照射模型（模拟ARC较为理想的模型）中是否存在Aβ的累积。2.在大鼠前房内注射Aβ，观察白内障发病情况，并研究其机制。3.在大鼠白内障建模过程中，向前房内注射SIRT1激活剂（可抑制Aβ生成），观察能否预防或延缓白内障的发生。本研究将揭示在体环境下Aβ在ARC发病中的作用及其机制，并为寻找ARC非手术干预方法奠定基础。

既往研究发现，ARC与 “淀粉样疾病”（最常见的淀粉样疾病为Alzeheimer病，AD）在发病机制上存在类同性，因此，淀粉样疾病发生中的关键物质β淀粉样蛋白（Aβ）受到了白内障领域研究者的关注。有研究表明，Aβ对淀粉样疾病的发展存在双向作用：Aβ过度累积可加速氧化损伤和疾病进展；而Aβ缺乏所导致其生理功能的缺陷也能够导致细胞凋亡和功能丧失。本项目主要研究年龄相关性白内障（ARC）发生、发展过程中Aβ在晶状体和房水中表达量的变化、以及Aβ对氧化环境下晶状体细胞凋亡的影响。研究发现，Aβ水平在ARC发生、发展的早、中期呈下降趋势，仅在最严重的核性重型ARC中才出现回升，但仍未超出正常晶状体晶状体内表达水平。究其原因，我们发现ARC患者的β-分泌酶活性显著下降，从而引起ARC发病早、中期Aβ生成减少。Aβ水平下调则引发了其前体APP蛋白的反馈性表达增加，在ARC终末期，随着Aβ表达量的回升，负反馈机制减弱，APP表达量恢复至接近正常水平。进一步研究发现，低浓度的Aβ能够提高氧化损伤环境下晶状体上皮细胞的活性。这些研究结果提示，存在于疾病早中期的Aβ水平的下降可能是加重晶状体上皮细胞凋亡的致病环节之一。