clusterin蛋白治疗脑淀粉样血管病变的探索性研究

The accumulation of aggregated Aβ40 on cerebral small arteries and capillaries, associated with immune-based vascular injury (especially complement activation), has played crucial role in the pathogenesis of cerebral amyloid angiopathy (CAA). Clusterin is an extracellular heat shock protein in the brain which has biological capacity of binding Aβ40 and membrane attack complex (C5b-9) to inhibit Aβ40 aggregation and complement activation, as well as Aβ40 clearance through brain blood barrier (BBB) via its receptor LRP2. Basically, our proposal is trying to increase the level of clusterin on vascular system by three methods: ventricular injection or infusion of recombinant clusterin protein, venous infusion of recombinant clusterin protein or its active peptide 113-122, or venous infusion of clusteirn antibody, in order to potentiate its biological function on Aβ40 aggregation, vascular clearance and complement activation, and hence manage to treat CAA effectively. Our study is a pilot investigation on the potential therapeutic effect of clusterin on CAA and we hope it will also be helpful for further exploration of the possibility of extracellular heat shock proteins in treating various kinds of human diseases.

Aβ40在脑小动脉和毛细血管的沉积及其继发的免疫系统（尤其是补体系统）的异常激活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；Clusterin蛋白是脑内固有的细胞外热休克蛋白，具有抑制Aβ40的聚集、补体反应（通过与膜攻击复合体C5b-9相结合）和加强Aβ40通过血管途径清除的作用。本研究拟通过三种方法，即脑室内注射人工合成Clusterin蛋白、血浆注射人工合成Clusterin蛋白或其活性肽链113-122,或血浆注射Clusterin蛋白特异性抗体，以达到增加脑微血管内Clusterin蛋白的含量，从而加强其对Aβ40聚集、清除和抑制补体反应的作用，明确其缓解CAA的生物效应。本课题是对Clusterin在中枢神经系统血管疾病如CAA中应用的探索性研究，意在为更多的细胞外热休克蛋白或其活性短应用提供新的理论和思路。

脑淀粉样血管病（CAA）是一种老年人中常见的颅内血管病变,其发病机制与Aβ40在小动脉和毛细血管的沉积及其继发的免疫系统的异常激活有关。本课题组以APP-PS1转基因小鼠（Tg6799）作为CAA的动物模型，探讨clusterin蛋白对CAA的治疗作用。我们发现脑室内持续注射Clusterin活性肽链D[113-122]2周，能显著减少Aβ40和Aβ42的沉积，改善记忆障碍。进一步的研究发现该活性肽链治疗后，Tg6799小鼠的脑组织的可溶性Aβ40和Aβ42浓度降低，LRP2受体蛋白表达增高，提示clusterin活性肽链D[113-122]的治疗作用可能通过LRP2介导的Aβ的清除途径。我们的研究结果为CAA的治疗开创了新的靶点，具有重要的意义。此外，在研究中，课题组发现Tg6799小鼠中，Ⅰ型补体受体蛋白（CR1）表达明显高于正常，在血管上表现为颗粒状，并与Aβ40共定位，提示CR1可能参与了淀粉样脑血管病变。这些研究结果为进一步探讨CAA的发病机制以及治疗提供了重要依据。