Regulatory T cell instability facilitates blood–brain barrier disruption via the β-catenin-tight junctions axis, leading to perioperative neurocognitive disorders

Abstract Perioperative neurocognitive disorders (PND) are significant neurological complications in elderly surgical patients, yet the underlying immune-mediated mechanisms remain elusive. Blood-brain barrier (BBB) disruption is increasingly recognized as a critical neurovascular event in PND and may result from perioperative immune dysregulation. Regulatory T cells (Tregs) are key mediators of neurovascular homeostasis and BBB integrity. We therefore investigated whether perioperative Treg instability contributed to BBB disruption and PND. Single-cell transcriptomic profiling of perioperative PBMCs from elderly surgical patients revealed marked remodeling of the CD4 + T-cell compartment, characterized by disproportionate loss of Tregs and functional destabilization. Tregs shifted from resting and immunosuppressive states toward an inflammatory-shifted state, accompanied by reduced expression of regulatory and tissue-reparative genes, including FOXP3 , CTLA4 , PDCD1 , and AREG . Comparative transcriptomic analysis of Tregs identified 34 dexmedetomidine-corrected genes, with CTNNB1 , encoding β-catenin, emerging as a prominent candidate hub within the protein–protein interaction network. These findings support β-catenin-associated signaling as an important regulatory pathway involved in perioperative Treg destabilization. Mouse hippocampal scRNA-seq revealed postoperative endothelial remodeling characterized by reduced S1pr1 and Cldn5 and increased Icam1 expression. In a murine PND model, β-catenin activation restored postoperative Treg abundance and regulatory gene expression while preserving hippocampal endothelial barrier programs, as evidenced by increased S1PR1 and Claudin-5 and reduced ICAM1 expression. These protective effects were markedly attenuated by PC61-mediated depletion of the Treg compartment, supporting an important Treg-dependent contribution. Furthermore, recombinant PD-L1-Fc treatment restored postoperative Treg abundance and was associated with preserved ultrastructural BBB integrity, reduced Evans blue-defined BBB leakage, attenuated hippocampal neuroinflammation, and improved cognitive function. These findings identify perioperative Treg instability as a prominent immune-associated contributor to BBB disruption and cognitive dysfunction. They further position Treg-associated β-catenin signaling as an important regulatory pathway contributing to the maintenance of neurovascular integrity.