Enhancing Purinergic Signaling at the Blood-Brain Barrier in Stroke: Bridging Murine and Human Ecto-Enzyme Dynamics

People involved: Jakob Körbelin, Maria Stamataki & Julia Lüschow in collaboration with the ERSI Lab, UKE

Background

The blood-brain barrier (BBB) plays a crucial role in regulating brain homeostasis and is a focal point in the study of neurodegenerative diseases and stroke. Fine-tuned purinergic signaling at the BBB is essential to maintain barrier integrity and regulate immune responses. By shaping the balance between extracellular ATP (pro-inflammatory) and adenosine (anti-inflammatory), the ectoenzymes CD39 and CD73 play an especially important role in regulating purinergic responses at the BBB. Interestingly, the expression of CD39 and CD73 significantly differs between brain endothelial cells from mice and humans which somewhat limits the significance of rodent BBB models in predicting disease outcome in humans.

Technology

Using our BBB-targeted AAV vector technology, we engineer murine brain endothelial cells to express CD73, the enzyme responsible for converting AMP into adenosine, a molecule known for its potent anti-inflammatory and neuroprotective properties. Assessing the outcome in the tMCAO stroke model, we aim to get a better understanding of the post-ischemic inflammatory response. By elevating CD73 expression to levels observed in humans, we hope to provide a more accurate model for human stroke, thus bridging the gap between animal models and human applications, particularly in how purinergic signaling affects the BBB and influences outcomes in stroke and neuroinflammation. The project elucidates the complex dynamics of purinergic signaling within the BBB and, ideally, establishes a novel platform for developing therapeutic strategies that target purinergic pathways to treat neurological disorders. The work on this project is funded by the German Research Foundation (DFG) as part of the Collaborative Centre SFB1328 (project A13).