Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.

Huang, X; Qi, J; Su, Y; Zhou, Y; Wang, Q; Huang, T; Xue, D; Zeng, Y; Verkhratsky, A; Zhou, B; Chen, H; Yi, C

Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.

Huang, X Qi, J Su, Y Zhou, Y Wang, Q Huang, T Xue, D Zeng, Y Verkhratsky, A Zhou, B Chen, H Yi, C

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Publisher:: Springer Nature
Publication Type:: Journal Article
Citation:: Cell Death Dis, 2024, 15, (4), pp. 258
Issue Date:: 2024-04-12

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Field	Value	Language
dc.contributor.author	Huang, X
dc.contributor.author	Qi, J
dc.contributor.author	Su, Y
dc.contributor.author	Zhou, Y
dc.contributor.author	Wang, Q
dc.contributor.author	Huang, T
dc.contributor.author	Xue, D
dc.contributor.author	Zeng, Y
dc.contributor.author	Verkhratsky, A
dc.contributor.author	Zhou, B
dc.contributor.author	Chen, H
dc.contributor.author	Yi, C
dc.date.accessioned	2024-06-17T09:41:00Z
dc.date.available	2024-04-02
dc.date.available	2024-06-17T09:41:00Z
dc.date.issued	2024-04-12
dc.identifier.citation	Cell Death Dis, 2024, 15, (4), pp. 258
dc.identifier.issn	2041-4889
dc.identifier.issn	2041-4889
dc.identifier.uri	http://hdl.handle.net/10453/179536
dc.description.abstract	The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer's disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/β-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APPswe/PS1dE9 mice) at the onset of amyloid-β (Aβ) accumulation. Toxic Aβ25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aβ25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/β-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.
dc.format	Electronic
dc.language	eng
dc.publisher	Springer Nature
dc.relation.ispartof	Cell Death Dis
dc.relation.isbasedon	10.1038/s41419-024-06639-0
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	Amyloid beta-Peptides
dc.subject.mesh	beta Catenin
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Brain
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Receptors, Tumor Necrosis Factor
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Brain
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	Receptors, Tumor Necrosis Factor
dc.subject.mesh	beta Catenin
dc.subject.mesh	Amyloid beta-Peptides
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Blood-Brain Barrier
dc.subject.mesh	Alzheimer Disease
dc.subject.mesh	beta Catenin
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Brain
dc.subject.mesh	Amyloid beta-Peptides
dc.title	Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.
dc.type	Journal Article
utslib.citation.volume	15
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1112 Oncology and Carcinogenesis
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
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-06-17T09:40:52Z
pubs.issue	4
pubs.publication-status	Published online
pubs.volume	15
utslib.citation.issue	4

Abstract:

The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer's disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/β-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APPswe/PS1dE9 mice) at the onset of amyloid-β (Aβ) accumulation. Toxic Aβ25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aβ25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/β-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.

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http://hdl.handle.net/10453/179536