The role and mechanisms of neuroinflammation and glucose metabolism in perioperative neurocognitive disorders

Abstract

The spectrum of cognitive dysfunction after surgery is now termed perioperative neurocognitive disorders (PNDs), previously known as postoperative cognitive dysfunction (POCD). PNDs can delay postoperative recovery and lower the quality of life for affected individuals, especially the elderly population. Considering the number of surgical procedures is on the rise and over one-third are performed on aged patients, PNDs are and will become a great burden on the health system. However, effective prevention or therapy are currently lacking. Emerging evidence shows that neuroinflammation and blood-brain barrier disruption are important pathological changes in the development PNDs. Our previous studies show rapid but transit increase of cytokines in the postsurgical brain and in the periphery, while the activation of glia is sustained and accompanied with cognitive deficits. However, how postoperative inflammatory responses contribute to the occurrence of postoperative cognitive deficits is not fully elucidated. Recent study explicates that cytokines can induce neurotoxic reactive astrocytes that are involved in the progress of neurodegenerative diseases by releasing complement factors. C3 is the central complement molecule and its excessive upregulation in neurological condition can result in synapse loss via microglia-mediated synaptic engulfment. Furthermore, glucose is the major energy supply of the brain and glucose transporter1 (GLUT1) is of special importance to the influx of glucose. Inflammatory responses with increase of cytokines in the periphery or the brain can disrupt the blood-brain barrier, especially GLUT1 in the endothelium, which affects glucose metabolism and deteriorates cognitive dysfunction in neurological diseases. However, few studies have evaluated the impact of C3 or GLUT1 on PNDs. Using a murine surgical model, I confirmed the presence of cognitive impairment following a laparotomy in both young and aged animals. The young mice displayed an obvious neuroinflammatory response with increased cytokines and glial activation in the hippocampus whereas the aged mice showed delayed systemic inflammation with increased cytokines in the periphery. To further evaluated the impact of astrocytic C3, reactive astrocytes from the hippocampi of the young mice were identified and verified as the neurotoxic phenotype with increase in C3. Reducing cerebral C3 by AAV9 delivery of C3 shRNA successfully preserved postoperative cognitive function by preventing microglia-mediated synaptic elimination in the hippocampus. In addition, the expression of GLUT1 in the blood-brain barrier endothelium was decreased in postsurgical aged mice, along with downregulation of tight junction proteins and lower level of glycolytic metabolites. AAV9-mediated conditional GLUT1 overexpression in blood-brain barrier successfully protected against cognitive impairment with partially improved glucose metabolism. These results demonstrated that surgery-induced neurotoxic reactive astrocytes promoted cognitive deficits by the release of C3 in young mice and that surgery-impaired GLUT1 in blood-brain barrier contributed to cognitive decline by affecting hippocampal glucose metabolism in aged mice, indicating that astrocytic C3 and GLUT1 in the blood-brain barrier could be potential therapeutic targets for PNDs.