Modulating neuroinflammation and cognitive function in postoperative cognitive dysfunction via CCR5-GPCRs-Ras-MAPK...

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Postoperative cognitive dysfunction (POCD) is a common and serious condition affecting elderly patients after surgery.
• Microglia play a critical role in neuroinflammation and neuronal integrity, processes implicated in POCD.
• Extracellular vesicles (EVs) are emerging as key mediators of intercellular communication in the central nervous system.

Purpose of the Study:

• To investigate the role of C-C chemokine receptor type 5 (CCR5) on microglial extracellular vesicles (EVs) in the pathogenesis of POCD.
• To determine how EVs derived from BV2 microglial cells with or without CCR5 influence neuroinflammation, neuronal integrity, and cognitive function in a POCD mouse model.

Main Methods:

• EVs were collected from BV2 microglial cells expressing CCR5 (EVs^M1) and from BV2 cells with CCR5 knockdown (EVs^M1-CCR5).
• These EVs were administered to mice subjected to POCD induction.
• Protein interactions, neuroinflammation markers, synaptic protein expression, dendritic spine morphology, and cognitive function (Morris Water Maze) were assessed.

Main Results:

• Interactions between CCR5, G-protein-coupled receptors (GPCRs), and Ras were confirmed, implicating the CCR5-GPCRs-Ras-MAPK pathway in neuroinflammation.
• EVs^M1 exacerbated neuroinflammation, reduced synaptic integrity, and impaired cognitive function in POCD mice.
• Conversely, EVs^M1-CCR5 attenuated neuroinflammation, preserved synaptic proteins and dendritic spines, and improved cognitive performance.

Conclusions:

• Microglial EVs mediate neuroinflammation and cognitive decline in POCD through the CCR5-GPCRs-Ras-MAPK pathway.
• Reducing CCR5 expression on microglial EVs confers neuroprotection and ameliorates POCD.
• Targeted modification of microglial EVs represents a promising therapeutic avenue for managing POCD.