Fibrinogen drives neuroinflammation and neuropathology in perioperative neurocognitive disorders

Blood-brain barrier (BBB) dysfunction and neuroimmune inflammatory response are persistent in patients with perioperative neurocognitive disorders (PND). Despite the clinical evidence, the mechanisms linking leaky BBB to neuropathology remain poorly understood. Fibrinogen, a BBB leakage-derived blood protein, is implicated in neurodegenerative diseases, but its role in PND and the underlying mechanisms are unknown.

Here, we established PND model in aged mice with exploratory laparotomy. Behavioral testing, BBB permeability detection, transcriptional changes, immunofluorescence staining and western blot were employed to discern the neuropathology in PND. BV2 cells were used for in vitro studies. Interventions included uPA administration, intracerebroventricular injection antibody, PI3K inhibitor administration.

Here, we show that fibrinogen binds to CD11b, which activates the PI3K/Akt/RhoA pathway in microglia, triggering neuroinflammation and cognitive deficits in aged PND model. In aged mice, fibrinogen is required for neurotoxic microglia polarization and proinflammatory factors increase after anesthesia and surgery. Antibody targeting fibrinogen-CD11b signaling provides protection from microglia activation and cognitive deficits in PND model.

Our study identifies fibrinogen-CD11b signaling as a critical mediator driving age-dependent neuroinflammation and neuropathology in PND. Targeting of this signaling may represent a therapeutic intervention for PND. Our findings link vascular leakage and neuroimmune activation, providing mechanistic insights for PND intervention strategies.