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

Respiratory infection with SARS-CoV-2 causes systemic vascular inflammation and cognitive impairment. In this study the authors sought to identify the underlying mechanisms mediating cerebrovascular dysfunction and inflammation following mild respiratory SARS-CoV-2 infection.

To this end, they conduced unbiased transcriptional analysis to identify brain endothelial cell signaling 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 signaling, a critical regulator of blood-brain barrier (BBB) integrity. The authors therefore hypothesized that enhancing cerebrovascular Wnt/β-catenin activity would offer protection against BBB permeability, neuroinflammation, and neurological signs in acute infection. Indeed, they 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 signaling or its downstream effectors could be potential interventional strategies for restoring cognitive health following viral infections.

Troy N Trevino, Avital B Fogel, Guliz Otkiran, Seshadri B Niladhuri, Mark A Sanborn, Jacob Class, Ali A Almousawi, Benoit Vanhollebeke, Leon M Tai, Jalees Rehman, Justin M Richner, Sarah E Lutz, Engineered Wnt7a ligands rescue blood–brain barrier and cognitive deficits in a COVID-19 mouse model, Brain, 2024;, awae031, https://doi.org/10.1093/brain/awae031