Amyloid beta-induced mitochondrial dysfunction and endothelial permeability in cerebral microvascular endothelial cells: The protective role of dexmedetomidine

Abstract

Postoperative cognitive dysfunction (POCD) is a common complication in patients who undergo anesthesia in different types of surgeries. Emerging evidence implicates elevated beta-amyloid (Aβ) in the pathogenesis of POCD. Meanwhile, Dexmedetomidine (DEX) has recently shown promise in reducing POCD incidence. This study aimed to elucidate the role of Aβ in inducing endothelial permeability in cerebral microvascular endothelial cells and the underlying mechanisms and testing the effects of DEX. We demonstrated that Aβ1–42, the prevalent Aβ form related to POCD, is cytotoxic to HBMECs, increasing transendothelial permeability and inducing mitochondrial dysfunction, as evidenced by elevated mitochondrial reactive oxygen species (ROS) and decreased ATP production and mitochondrial membrane potential. Furthermore, Aβ1–42 was shown to inhibit Sirt3, exacerbating mitochondrial dysfunction. Conversely, DEX was found to prevent Aβ1–42-induced mitochondrial dysfunction and permeability increases and preserved tight junction proteins in HBMECs.These findings suggest that DEX, as a Sirt3 activator, may offer a pharmacological strategy to mitigate Aβ1–42-related cerebral microvascular endothelial cell dysfunction and preserve cognitive function post-surgery.

Keywords

• Postoperative cognitive dysfunction (POCD)
• Amyloid-β (Aβ)
• HBMECs
• Sirt3
• Blood–brain barrier (BBB) permeability
• Dexmedetomidine (DEX)