Changhua Qu1, Linling Xu1, Jun Shen1, Yaqing Li1, Chujie Qu1, Hao Song1, Junjian Zhang2. 1. Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, Hubei 430071, China. 2. Department of Neurology, Zhongnan Hospital, Wuhan University, No.169, Donghu Road, Wuhan, Hubei 430071, China. Electronic address: wdsjkx@163.com.
Abstract
BACKGROUND: Chronic 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. METHODS: Rats 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. RESULTS: After 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. CONCLUSIONS: These 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.
BACKGROUND:Chronic 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. METHODS:Rats 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. RESULTS: After 2VO, CCHrats 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. CONCLUSIONS: These 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.