Modulating neuroinflammation and cognitive function in postoperative cognitive dysfunction via CCR5‐GPCRs‐Ras‐MAPK pathway targeting with microglial EVs

Abstract Aims Postoperative cognitive dysfunction (POCD) is prevalent among the elderly, characterized primarily by cognitive decline after surgery. This study aims to explore how extracellular vesicles (EVs) derived from BV2 microglial cells, with and without the C‐C chemokine receptor type 5 (CCR5), affect neuroinflammation, neuronal integrity, and cognitive function in a POCD mouse model. Methods We collected EVs from LPS‐stimulated BV2 cells expressing CCR5 (EVs M1 ) and from BV2 cells with CCR5 knockdown (EVs M1‐CCR5 ). These were administered to POCD‐induced mice. Protein interactions between CCR5, G‐protein‐coupled receptors (GPCRs), and Ras were analyzed using structure‐based docking and co‐immunoprecipitation (Co‐IP). We assessed the phosphorylation of p38 and Erk, the expression of synaptic proteins PSD95 and MAP2, and conducted Morris Water Maze tests to evaluate cognitive function. Results Structure‐based docking and Co‐IP confirmed interactions between CCR5, GPR, and Ras, suggesting a CCR5‐GPCRs‐Ras‐MAPK pathway involvement in neuroinflammation. EVs M1 heightened neuroinflammation, reduced synaptic integrity, and impaired cognitive function in POCD mice. In contrast, EVs M1‐CCR5 reduced neuroinflammatory markers, preserved synaptic proteins, enhanced dendritic spine structure, and improved cognitive outcomes. Conclusion EVs M1 induced neuroinflammation via the CCR5‐GPCRs‐Ras‐MAPK pathway, with EVs M1‐CCR5 showing protective effects on POCD progression, suggesting a new therapeutic strategy for POCD management via targeted modification of microglial EVs.