| Title: |
Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model |
| Authors: |
Trevino, Troy N; Fogel, Avital B; Otkiran, Guliz; Niladhuri, Seshadri B; Sanborn, Mark A; Class, Jacob; Almousawi, Ali A; Vanhollebeke, Benoit; Tai, Leon M; Rehman, Jalees; Richner, Justin M; Lutz, Sarah E |
| Source: |
Brain ; volume 147, issue 5, page 1636-1643 ; ISSN 0006-8950 1460-2156 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2024 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/brain/awae031 |
| DOI: |
10.1093/brain/awae031/57297727/awae031.pdf |
| Availability: |
https://doi.org/10.1093/brain/awae031; https://academic.oup.com/brain/advance-article-pdf/doi/10.1093/brain/awae031/57297727/awae031.pdf; https://academic.oup.com/brain/article-pdf/147/5/1636/57397436/awae031.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.B62AACC4 |
| Database: |
BASE |