Engineered Wnt7a ligands rescue blood-brain barrier and cognitive deficits in a COVID-19 mouse model.

Autor:	Trevino TN; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Fogel AB; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Otkiran G; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Niladhuri SB; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Sanborn MA; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Class J; Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Almousawi AA; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Vanhollebeke B; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles (ULB), Gosselies B-6041, Belgium., Tai LM; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Rehman J; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Richner JM; Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA., Lutz SE; Department of Anatomy and Cell Biology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 May 03; Vol. 147 (5), pp. 1636-1643.
DOI:	10.1093/brain/awae031
Abstrakt:	Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. We sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection. To this end, we performed unbiased transcriptional analysis to identify brain endothelial cell signalling pathways dysregulated by mouse adapted SARS-CoV-2 MA10 in aged immunocompetent C57Bl/6 mice in vivo. This analysis revealed significant suppression of Wnt/β-catenin signalling, a critical regulator of blood-brain barrier (BBB) integrity. We therefore hypothesized that enhancing cerebrovascular Wnt/β-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, we found that delivery of cerebrovascular-targeted, engineered Wnt7a ligands protected BBB integrity, reduced T-cell infiltration of the brain, and reduced microglial activation in SARS-CoV-2 infection. Importantly, this strategy also mitigated SARS-CoV-2 induced deficits in the novel object recognition assay for learning and memory and the pole descent task for bradykinesia. These observations suggest that enhancement of Wnt/β-catenin signalling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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