sVCAM1 in the Hippocampus Contributes to Postoperative Cognitive Dysfunction in Mice by Inducing Microglial...

Area of Science:

• Neuroscience
• Immunology
• Molecular Biology

Background:

• Postoperative cognitive dysfunction (POCD) is a significant postsurgical complication with unclear mechanisms.
• Neuroinflammation, driven by microglial activation, is implicated in POCD.
• Vascular cell adhesion molecule 1 (VCAM1) upregulation correlates with microglial activation in the hippocampus, but its role is unknown.

Purpose of the Study:

• To investigate the role of soluble VCAM1 (sVCAM1) in triggering hippocampal microglial activation and contributing to POCD.
• To test the hypothesis that sVCAM1 activates the very late antigen-4 (VLA-4) receptor, leading to microglial activation and cognitive dysfunction.

Main Methods:

• Assessed VCAM1 and sVCAM1 expression in mouse hippocampus post-surgery.
• Measured serum sVCAM1 levels in mice and humans.
• Administered anti-VCAM1 and anti-VLA-4 treatments in vivo.
• Utilized in vitro BV2 cell models with recombinant sVCAM1 and VLA-4 blockade.
• Analyzed microglial activation, cytokine production, VLA-4 expression, and P38 MAPK pathway activation.

Main Results:

• Surgery upregulated hippocampal VCAM1 and sVCAM1, correlating with microglial activation.
• Serum sVCAM1 increased post-surgery in mice and humans.
• Anti-VCAM1 and anti-VLA-4 treatments reduced microglial activation, inflammation, and cognitive deficits.
• In vitro, sVCAM1 induced M1 polarization and activated the P38 MAPK pathway in BV2 cells, effects reversed by VLA-4 blockade.

Conclusions:

• Elevated hippocampal sVCAM1 contributes to surgery-induced microglial activation and cognitive dysfunction.
• The sVCAM1-VLA-4 interaction in microglia is a key mechanism in POCD.
• Inhibiting the sVCAM1-VLA-4 pathway presents a potential therapeutic strategy for POCD.