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

Wang, Q; Huang, X; Su, Y; Yin, G; Wang, S; Yu, B; Li, H; Qi, J; Chen, H; Zeng, W; Zhang, K; Verkhratsky, A; Niu, J; Yi, C

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

Wang, Q Huang, X Su, Y Yin, G Wang, S Yu, B Li, H Qi, J Chen, H

Zeng, W Zhang, K Verkhratsky, A Niu, J Yi, C

Permalink

Publisher:: Oxford University Press (OUP)
Publication Type:: Journal Article
Citation:: Brain, 2022
Issue Date:: 2022-07-05

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Accepted versionAdobe PDF (2.55 MB)

View on publisher's site

View statistics

Full metadata record

Field	Value	Language
dc.contributor.author	Wang, Q
dc.contributor.author	Huang, X
dc.contributor.author	Su, Y
dc.contributor.author	Yin, G
dc.contributor.author	Wang, S
dc.contributor.author	Yu, B
dc.contributor.author	Li, H
dc.contributor.author	Qi, J
dc.contributor.author	Chen, H https://orcid.org/0000-0001-6883-3752
dc.contributor.author	Zeng, W
dc.contributor.author	Zhang, K
dc.contributor.author	Verkhratsky, A
dc.contributor.author	Niu, J
dc.contributor.author	Yi, C
dc.date.accessioned	2022-07-08T05:46:58Z
dc.date.available	2022-06-14
dc.date.available	2022-07-08T05:46:58Z
dc.date.issued	2022-07-05
dc.identifier.citation	Brain, 2022
dc.identifier.issn	0006-8950
dc.identifier.issn	1460-2156
dc.identifier.uri	http://hdl.handle.net/10453/158758
dc.description.abstract	Alzheimer's disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD. Here, we showed dysfunctional BBB in AD patients 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 (BECs). In the APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and Aβ-treated BECs, we found suppressed Wnt/β-catenin signaling 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 signaling) to activate Wnt/β-catenin pathway, BBB malfunction was restored by preventing Aβ-induced BEC impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate BBB malfunction induced by Aβ, which may be a potential treatment strategy for AD.
dc.language	eng
dc.publisher	Oxford University Press (OUP)
dc.relation.ispartof	Brain
dc.relation.isbasedon	10.1093/brain/awac236
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences
dc.subject.classification	Neurology & Neurosurgery
dc.title	Activation of Wnt/β-catenin pathway mitigates blood-brain barrier dysfunction in Alzheimer's disease.
dc.type	Journal Article
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	17 Psychology and Cognitive Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.date.updated	2022-07-08T05:46:57Z
pubs.publication-status	Published online

Abstract:

Alzheimer's disease (AD) is a neurodegenerative disorder that causes age-dependent neurological and cognitive declines. The treatments for AD pose a significant challenge, because the mechanisms of disease are not being fully understood. Malfunction of the blood-brain barrier (BBB) is increasingly recognized as a major contributor to the pathophysiology of AD, especially at the early stages of the disease. However, the underlying mechanisms remain poorly characterized, while few molecules can directly target and improve BBB function in the context of AD. Here, we showed dysfunctional BBB in AD patients 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 (BECs). In the APPswe/PS1dE9 (APP/PS1) mouse model of AD, BBB dysfunction started at 4 months of age and became severe at 9 months of age. In the cerebral microvessels of APP/PS1 mice and Aβ-treated BECs, we found suppressed Wnt/β-catenin signaling 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 signaling) to activate Wnt/β-catenin pathway, BBB malfunction was restored by preventing Aβ-induced BEC impairments and promoting the barrier repair. In conclusion, targeting LRP6 in the Wnt/β-catenin pathway in the brain endothelium can alleviate BBB malfunction induced by Aβ, which may be a potential treatment strategy for AD.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/158758