“glymphatic系统”在蛛网膜下腔出血后认知功能障碍中的作用及其机制研究

The incidence of cognitive dysfunction is very high in the survivors of subarachnoid hemorrhage (SAH), but its pathogenesis is yet to be identified. Studies have shown that cerebral tau was elevated and amyloid beta-protein was decreased in the cerebrospinal fluid of SAH patient, which were similar to Alzheimer's disease. The “glymphatic system (GS)” is a recently discovered new pathway for metabolite clearance and its functional impairment is involved in the pathological process of various cognitive dysfunction related diseases. Previously, we have confirmed that the GS was widely involved in the pathological process of various complications after SAH, and accompanied with its functional impairment. We thus speculate the GS impairemed in acute and chronic phase induced by SAH is key factor for cognitive dysfunction, and treatment strategy targeting the GS can improve the cognitive dysfunction after SAH. Using two-photon microscope and CLARITY technology platform, we explore the pathological mechanism of the GS and the protective effect of targeting it as a therapeutic strategy in cognitive dysfunction after SAH with real-time, dynamic and three-dimensional image. By identifying the pathological effect of GS, we hope to clarify the pathophysiological mechanism of cognitive dysfunction after SAH and establish a novel therapeutic strategy which targets the GS, which is of important significance in lessening SAH burdens for patients and community.

认知功能障碍在蛛网膜下腔出血(SAH)存活者中的发病率极高，其机制未明。研究显示SAH患者脑脊液可见Tau含量升高、Aβ含量降低，这些改变与Alzheimer病极为类似。脑内的“glymphatic系统(GS)”是最近发现的脑代谢废弃物清除的新渠道，其功能损伤参与了多种认知功能障碍相关疾病的病理过程。我们前期发现，GS广泛参与了SAH急性期多种并发症的病理过程，并伴有功能损害。因此推测SAH所致急慢性期的GS功能损害是SAH后认知功能障碍发生的关键因素，靶向该系统的治疗可减轻SAH后认知功能障碍。本项目拟利用双光子活体成像和CLARITY技术，实时、动态、三维的探讨GS在SAH后认知功能障碍中的病理作用及其机制，并探索急性期靶向该系统的治疗对SAH后认知功能障碍的保护作用。本项目完成对阐明SAH后认知功能障碍的发病机制，研发靶向该系统的治疗策略，减轻由SAH所引起的社会负担有着重要的意义。

Glymphatic系统是新近发现的脑内液体引流系统，可以清除脑内溶质及促进营养物质在脑内的分布。该系统广泛参与了SAH后的多种并发症的病理过程，但其是否参与了SAH后认知功能障碍的发病过程尚未明确。本项目旨在明确SAH急慢性期均存在“glymphatic系统”功能损害，为深入理解SAH后认知功能障碍的发病机制提供全新的视角；探讨“glymphatic系统”在SAH后认知功能障碍中的病理作用及其机制，为开发基于“glymphatic系统”的预防和治疗SAH后认知功能障碍的策略提供坚实的理论基础；探索急性期rt-PA治疗对SAH后认知功能的保护作用，同时搭建靶向glymphatic系统，改善SAH后认知功能障碍的药物筛选平台，为进一步研发有效防治SAH后认知功能障碍的药物提供可靠的技术平台。我们的研究表明，随着时间的延长，SAH小鼠神经功能缺损、神经细胞损伤认知功能下降逐渐加重，AQP-4极性和表达逐渐下降，Aβ1-40逐渐积累，于3m时最显著；外源性给予Aβ1-40导致上述变化更加明显；rt-PA治疗后可增加AQP-4的表达和极性，减少Aβ1-40积累，改善SAH小鼠认知功能。结论：小鼠SAH后AQP-4表达和极性降低，使得高度依赖AQP-4的glymphatic系统损伤，造成脑内Aβ清除减少、聚集过多，可能导致远期出现认知功能障碍。rt-PA治疗可改善glymphatic系统功能，从而改善SAH后认知功能障碍。