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Neurochemical Research

Neurochemical Research

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Caveolin-1-Mediated Blood-Brain Barrier Disruption via MMP2/9 Contributes to Postoperative Cognitive Dysfunction.

Published:26 June 2025 DOI: 10.1007/s11064-025-04458-z PMID: 40571858
Xinrui Li,?Weihua Ding,?Xia Zhang,?Xiaodong Tang,?Yueying Zheng,?Yi Ma,?Xiuxia Bao,?Xianhui Kang,?Shengmei Zhu

Abstract

Postoperative cognitive dysfunction (POCD) is a prevalent complication following major surgery, particularly in older adults, and is associated with increased morbidity, prolonged hospitalization, and reduced quality of life. Although blood-brain barrier (BBB) disruption has been implicated in POCD pathogenesis, the molecular mechanisms remain poorly defined. In this study, we identify Caveolin-1 (Cav-1), a membrane scaffolding protein highly expressed in endothelial cells (ECs), as a key regulator of BBB integrity and cognitive function following surgical trauma. Using a tibial fracture internal fixation model in mice, we observed a significant upregulation of Cav-1 in the hippocampus, accompanied by reduced expression of tight junctions (TJs) proteins (Claudin-5 and ZO-1), increased BBB permeability, and impaired performance in behavioral assays indicative of cognitive decline. Pharmacological inhibition of Cav-1 via methyl-β-cyclodextrin (MβCD) attenuated these effects, restoring TJs expression, reducing BBB leakage, and improving cognitive outcomes. To elucidate the underlying mechanism, we employed an in vitro inflammation model using LPS-stimulated brain microvascular ECs. Cav-1 upregulation was found to increase the expression of matrix metalloproteinases MMP2 and MMP9, which in turn degraded TJs. Inhibition of Cav-1 suppressed MMP2/9 expression and preserved barrier integrity, confirming a Cav-1/MMP2/9 signaling axis. These findings demonstrate that Cav-1 plays a central role in mediating BBB breakdown and postoperative cognitive impairment via MMP-dependent degradation of TJs. Targeting Cav-1 may offer a novel therapeutic strategy to preserve BBB function and reduce the incidence of POCD in surgical patients.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
beta-Cyclodextrin methyl ethers 128446-36-6 C54H94O35 430 suppliers $5.00-$14610.00
beta-Cyclodextrin methyl ethers 128446-36-6 C54H94O35 430 suppliers $5.00-$14610.00
beta-Cyclodextrin methyl ethers 128446-36-6 C54H94O35 430 suppliers $5.00-$14610.00
beta-Cyclodextrin methyl ethers 128446-36-6 C54H94O35 430 suppliers $5.00-$14610.00
beta-Cyclodextrin methyl ethers 128446-36-6 - Inquiry
beta-Cyclodextrin methyl ethers 128446-36-6 - Inquiry
Methyl-b-cyclodextrin 128446-36-6 - Inquiry
Methyl-b-cyclodextrin 128446-36-6 - Inquiry

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