D30 alleviates β2-microglobulin -facilitated neurotoxic microglial responses in isoflurane/surgery-induced cognitive dysfunction in aged mice.

Abstract

Post-operative cognitive dysfunction (POCD) is a common complication with no effective treatment in elderly patients. POCD and Alzheimer's disease (AD), and many other cognitive diseases mostly involve neurotoxic microglia response, and recently, β2-microglobulin (B2M) has been suggested to play a pivotal role. A novel pyromeconic acid-styrene hybrid compound D30 was synthesized by our team and shown to be safe and effective in some neurodegenerative mouse models. Here we evaluated D30 on POCD and its potential mechanism. 14-18month-old male C57BL/6 mice were used to establish POCD through isoflurane anesthesia and surgery. Elderly patients' plasmas were collected pre- and post-operatively. Primary mouse microglia were subjected to various stimulations in multiple experimental designs to imitate in vivo POCD-like conditions. Morris water maze, fear conditioning, western blot, immunofluorescent staining, and blood-brain-barrier (BBB) permeability were conducted in this study. D30 administration significantly improved learning and memory in aged mice following POCD. While neurotoxic M1 microglia cells were dramatically increased following POCD, manifested as morphologically changing into fewer and shorter branches, enlarged somatic areas, and upregulated expression of iNOS and C1q, Notably, following POCD, B2M was significantly upregulated in the plasma and the brain. D30 treatment significantly suppressed these pathological changes, by inhibiting the POCD-induced BBB breakdown while suppressing the surge of plasma B2M levels. D30 treatment suppressed POCD- induced surge of B2M and Aβ plaques in the brain, preserved adult hippocampal neurogenesis vulnerable to POCD. Furthermore, post-operative levels of B2M were significantly elevated over the preoperative levels in patients aged over 80 years and over. In parallel to mouse plasma after POCD, the post-operative patient plasma was also much more effective at activating M1 microglia. Of note, these POCD plasma-induced activation of M1 microglia were largely prevented by D30 treatment. Taken together, by inhibiting the surge of plasma B2M, protecting BBB integrity, and reducing inflammatory response, D30 protected aged mice from B2M-facilitated POCD.