CD73-derived adenosine at the blood-brain barrier confers protection in a mouse model of ischemic stroke

Stamataki, M.; Costanzo, E. M.; Luschow, J.; Hiefner, J.; Veltkamp, A.; Riecken, K.; Mummert, T.; Kaul, M.; Saygi, C.; Alawi, M.; Worthmann, A.; Rissiek, B.; Magnus, T.; Korbelin, J.

doi:10.64898/2026.06.19.732935

bioRxiv · 10.64898/2026.06.19.732935

CD73-derived adenosine at the blood-brain barrier confers protection in a mouse model of ischemic stroke

Stamataki, M.·Costanzo, E. M.·Luschow, J.·Hiefner, J.·Veltkamp, A.·Riecken, K.·Mummert, T.·Kaul, M.·Saygi, C.·Alawi, M.·Worthmann, A.·Rissiek, B.·Magnus, T.·Korbelin, J.

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Abstract

Ischemic stroke remains a leading cause of death and disability, and current reperfusion therapies do not address the secondary neuroinflammatory response following blood-brain barrier (BBB) disruption. Purinergic signaling critically regulates this process: extracellular ATP promotes inflammation, whereas its enzymatic conversion into adenosine exerts tissue-protective effects. Notably, the ectonucleotidase CD73 (NT5E), which catalyzes AMP-to-adenosine conversion, is highly expressed by human but not murine brain endothelial cells (BECs). Here, we investigated the role of endothelial CD73 in ischemic stroke using an AAV vector engineered for selective transduction of murine BECs to induce BBB-specific CD73 expression. Endothelial CD73 enhanced extracellular ATP degradation toward adenosine generation and established a purine metabolism profile resembling that of human BECs. In the transient middle cerebral artery occlusion (tMCAO) mouse model, BBB-targeted CD73 expression reduced infarct volume by 40% and prevented early mortality within 48 h after reperfusion. Transcriptomic and flow cytometric analyses revealed altered leukocyte responses, including increased recruitment of monocytes/macrophages whose gene expression signatures were consistent with inflammation-resolving programs. These findings identify endothelial CD73 as an important regulator of post-ischemic neuroinflammation and highlight species-specific differences in BBB purine metabolism with implications for translational stroke research.

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Stamataki, M., Costanzo, E. M., Luschow, J., Hiefner, J., Veltkamp, A., Riecken, K., Mummert, T., Kaul, M., Saygi, C., Alawi, M., Worthmann, A., Rissiek, B., Magnus, T., Korbelin, J.. 2026-06-24. CD73-derived adenosine at the blood-brain barrier confers protection in a mouse model of ischemic stroke. https://doi.org/10.64898/2026.06.19.732935

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