Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion
Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion
复制标题
保护血脑屏障作为丰富环境改善慢性脑灌注不足引起的认知障碍的潜在机制
DOI：
10.1016/j.bbr.2019.112385
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发表时间：
2019-11
期刊：
影响因子：
--
通讯作者：
Junjian Zhang
中科院分区：
文献类型：
--
作者：
Changhua Qu;Linling Xu;Jun Shen;Yaqing Li;Chujie Qu;Hao Song;Junjian Zhang
慢性脑低灌注（CCH）是阿尔茨海默病（AD）和血管性痴呆（VD）早期共同的病理生理基础。血脑屏障（blood-brain barrier，BBB）的破坏已被证实是CCH相关认知障碍的一个重要因素。在这里，我们探讨了丰富的环境（EE）干预对CCH引起的血脑屏障破坏和认知障碍，和潜在的mechanism.MethodsRats在EE组暴露于EE，而标准环境（SE）组保持在一个标准的笼子里，床上用品，但没有其他对象的影响。第14天，通过永久性双侧颈总动脉闭塞（2 VO）诱导CCH。接着，通过化学比色法测量海马中的伊文思蓝（EB）渗漏以动态评估BBB通透性。第28天，透射电镜观察血脑屏障超微结构。采用Western-blotting技术检测BBB完整性相关蛋白、基质金属蛋白酶-2/-9（MMP-2/-9）和经典Wnt/β-catenin信号通路相关蛋白的表达水平。结果2 VO后，暴露于SE的CCH大鼠出现明显的认知功能障碍和血脑屏障破坏。BBB损伤表现为EB渗漏增加、超微结构破坏、BBB完整性相关蛋白降解和MMP-2/-9上调。这些变化在EE干预后显著减轻。此外，EEs还能激活大鼠海马Wnt/β-catenin信号通路。结论EEs可能通过激活Wnt/β-catenin信号通路，保护血脑屏障，从而改善大鼠认知功能障碍。
BackgroundChronic cerebral hypoperfusion (CCH) is a common pathophysiological basis for Alzheimer’s Disease and vascular dementia in the early stages. It has been confirmed that blood-brain barrier (BBB) destruction is a key factor in CCH-related cognitive impairment. Here we explored the effects of an enriched environment (EE) intervention on CCH-induced BBB destruction and cognitive impairment, and the underlying mechanism.MethodsRats in the EE group were exposed to an EE, while the standard environment (SE) group was maintained in a standard cage with bedding but no other objects. On day 14, CCH was induced via permanent bilateral common carotid artery occlusion (2VO). Next, Evans blue (EB) leakage in the hippocampus was measured by chemical colorimetry to dynamically evaluate BBB permeability. On day 28, the BBB ultrastructure was observed using transmission electron microscopy. The expression levels of BBB integrity-related proteins, matrix metalloproteinases-2/-9 (MMP-2/-9), and the classical Wnt/β-catenin signaling pathway-related proteins were detected using western-blotting techniques. On day 43, cognitive function was assessed using the Morris water maze.ResultsAfter 2VO, CCH rats exposed to the SE developed obvious cognitive impairment and BBB destruction. BBB damage was manifested through increased EB leakage, ultrastructural destruction, degradation of BBB integrity-related proteins, and up-regulation of MMP-2/-9. These changes were significantly alleviated after the EE intervention. In addition, EEs activated the Wnt/β-catenin signaling pathway in the hippocampus of rats.ConclusionsThese results suggest that protection of the BBB may be a novel mechanism by which EEs ameliorate CCH-induced cognitive impairment, and this effect may be related to the activation of the Wnt/β-catenin pathway.
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