Wnt信号通路
血脑屏障
神经科学
海马体
背景(考古学)
阿尔茨海默病
痴呆
医学
生物
细胞生物学
疾病
内科学
信号转导
中枢神经系统
古生物学
作者
Qi Wang,Xiaomin Huang,Yixun Su,Guowei Yin,Shouyu Wang,Bin Yu,Hui Li,Junhua Qi,Hui Chen,Wen Zeng,Kai Zhang,Alexei Verkhratsky,Jianqin Niu,Chenju Yi
出处
期刊:Brain
[Oxford University Press]
日期:2022-07-05
卷期号:145 (12): 4474-4488
被引量:48
标识
DOI:10.1093/brain/awac236
摘要
Abstract Alzheimer’s disease is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for Alzheimer’s disease pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood–brain barrier is increasingly recognized as a major contributor to the pathophysiology of Alzheimer’s disease, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve blood–brain barrier function in the context of Alzheimer’s disease. Here, we showed dysfunctional blood–brain barrier in patients with Alzheimer’s disease reflected by perivascular accumulation of blood-derived fibrinogen in the hippocampus and cortex, accompanied by decreased tight junction proteins Claudin-5 and glucose transporter Glut-1 in the brain endothelial cells. In the APPswe/PS1dE9 (APP/PS1) mouse model of Alzheimer’s disease, blood–brain barrier dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and amyloid-β-treated brain endothelial cells, we found suppressed Wnt/β-catenin signalling triggered by an increase of GSK3β activation, but not an inhibition of the AKT pathway or switching to the Wnt/planar cell polarity pathway. Furthermore, using our newly developed optogenetic tool for controlled regulation of LRP6 (upstream regulator of the Wnt signalling) to activate Wnt/β-catenin pathway, blood–brain barrier malfunction was restored by preventing amyloid-β-induced brain endothelial cells impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate blood–brain barrier malfunction induced by amyloid-β, which may be a potential treatment strategy for Alzheimer’s disease.
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