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Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease

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 increasi...

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Autores principales: Wang, Qi, Huang, Xiaomin, Su, Yixun, Yin, Guowei, Wang, Shouyu, Yu, Bin, Li, Hui, Qi, Junhua, Chen, Hui, Zeng, Wen, Zhang, Kai, Verkhratsky, Alexei, Niu, Jianqin, Yi, Chenju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762951/
https://www.ncbi.nlm.nih.gov/pubmed/35788280
http://dx.doi.org/10.1093/brain/awac236
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author Wang, Qi
Huang, Xiaomin
Su, Yixun
Yin, Guowei
Wang, Shouyu
Yu, Bin
Li, Hui
Qi, Junhua
Chen, Hui
Zeng, Wen
Zhang, Kai
Verkhratsky, Alexei
Niu, Jianqin
Yi, Chenju
author_facet Wang, Qi
Huang, Xiaomin
Su, Yixun
Yin, Guowei
Wang, Shouyu
Yu, Bin
Li, Hui
Qi, Junhua
Chen, Hui
Zeng, Wen
Zhang, Kai
Verkhratsky, Alexei
Niu, Jianqin
Yi, Chenju
author_sort Wang, Qi
collection PubMed
description 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 APP(swe)/PS1(dE9) (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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spelling pubmed-97629512022-12-20 Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease Wang, Qi Huang, Xiaomin Su, Yixun Yin, Guowei Wang, Shouyu Yu, Bin Li, Hui Qi, Junhua Chen, Hui Zeng, Wen Zhang, Kai Verkhratsky, Alexei Niu, Jianqin Yi, Chenju Brain Original Article 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 APP(swe)/PS1(dE9) (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. Oxford University Press 2022-07-05 /pmc/articles/PMC9762951/ /pubmed/35788280 http://dx.doi.org/10.1093/brain/awac236 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Wang, Qi
Huang, Xiaomin
Su, Yixun
Yin, Guowei
Wang, Shouyu
Yu, Bin
Li, Hui
Qi, Junhua
Chen, Hui
Zeng, Wen
Zhang, Kai
Verkhratsky, Alexei
Niu, Jianqin
Yi, Chenju
Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title_full Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title_fullStr Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title_full_unstemmed Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title_short Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease
title_sort activation of wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in alzheimer’s disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9762951/
https://www.ncbi.nlm.nih.gov/pubmed/35788280
http://dx.doi.org/10.1093/brain/awac236
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