红细胞CR1介导的Aβ40清除途径对治疗脑淀粉样血管病变的探索性研究

The accumulation of aggregated Aβ40 in cerebral small arteries and capillaries, associated with complement system changes, played important role in pathogenesis of cerebral amyloid angiopathy (CAA). Aβ40 can activate complement system which is characterized by C3 production enhancement and converted into C3a and C3b after activation. CR1 on membrane of erythrocyte in the circulation system can bind protein opsonized by C3b and transport it to liver for degradation. So in our study, we hypothesized and tried to testify that erythrocyte CR1 degradation system was involved in clearance of Aβ40 in CAA animal model (Tg2576 transgenic mouse). In addition, we used sCR1 and CR1 antibody to increase or block the function of CR1 in order to investigate whether modulating complement system by targeting on CR1 will improve the cognitive function, cerebral vascular function and severity of CAA in Tg2576 mouse. Finally, we also studied the changes of other Aβ40 clearance systems after CR1 modulation, which included LRP-1, RAGE, clusterin transport system and interstitial fluid lymphatic drainage. We hope this will provide important data for further exploring the possibility of combination therapy in CAA.

Aβ40在脑小动脉和毛细血管的沉积及其继发的补体系统异常在脑淀粉样血管病变（Cerebral amyloid angiopathy, CAA）的发病机制中具有重要的作用。Aβ40能激活血液中的C3补体分子，促进C3分解为C3a和C3b，继而激活补体系统。红细胞膜上的CR1能与C3b调理素化蛋白结合，介导血液中多种异常蛋白或多肽分子运送至肝脏系统进行降解。本研究提出红细胞膜CR1蛋白参与Aβ40的血液系统的清除途径的假说，并以Tg2576转基因小鼠为模型进行验证。此外，本研究将用sCR1和CR1特异性抗体，增强或阻断CR1蛋白与C3b调理素化Aβ40的结合，来观察对CAA的治疗作用。最后，本研究在调控CR1蛋白的同时，观察Aβ40的其他清除途径的改变，如LRP-1、RAGE、clusterin和组织间液的淋巴回流，为探索CAA的联合治疗提供新的理论和思路。

脑淀粉样血管病（Cerebral amyloid angiopathy, CAA）是引起老年人常见的颅内血管病变，与Aβ40在脑小动脉和毛细血管的沉积密切相关。脑内存在多条Aβ40的清除途径，其中包括红细胞膜CR1介导的清除途径。本课题组用人外周血，发现部分红细胞膜上同时携带CR1-C3b-Aβ40蛋白，其CR1存在两种异构体，具有不同的携带C3b位点，并用人群队列研究，发现CR1异构体与脑内CAA特征性影像改变脑微出血显著相关。我们进一步以APP-PS1转基因小鼠为动物模型，发现外周血红细胞膜上的CR1同源蛋白--Crry蛋白表达显著增高，与脑内Aβ40聚集的CAA呈正相关。这些研究结果证实了CR1-C3b-Aβ40清除途径参与了CAA的形成。用慢性睡眠剥夺作为生理性刺激增高小鼠的Crry蛋白，发现转基因小鼠无法象野生小鼠一样继续激活Crry蛋白清除系统，提示转基因小鼠的红细胞膜上CR1介导的Aβ40清除系统调节发生异常。我们的研究提出了CR1介导的Aβ40的清除途径异常在CAA发病机制中的重要作用，为探索CAA的生物学标记物和治疗提供新的理论和思路。