Recombinant Adiponectin Peptide Ameliorates Cortical Neuron Damage Induced by Chronic Cerebral Hypoperfusion by Inhibiting NF-κB Signaling and Regulating Microglial Polarization

Abstract

\n Background Chronic cerebral hypoperfusion (CCH) is common in multiple central nervous system diseases that are associated with neuronal death and cognitive impairment. Microglial activation-mediated polarization changes may be involved in CCH-induced neuronal damage. Adiponectin (APN) is a fat-derived plasma protein that affects neuroprotection. This study investigated whether a recombinant APN peptide (APN-P) improved the cognitive function of CCH rats by regulating microglial polarization in the cortex. Methods A CCH rat model was established through bilateral common carotid artery occlusion (BCCAO) surgery. An antibody microarray was used to analyze differentially expressed proteins in the cerebral cortex of CCH rats compared to the sham rats. APN-P and a solvent control were used to intervene at different time points. Western blotting and immunofluorescence staining were conducted to examine the status of microglial polarization in different treatment groups. qRT-PCR was used to detect the expression levels of inflammatory and anti-inflammatory genes. Neuronal morphology was assessed via Nissl staining, and cognitive function was assessed with the Morris water maze test. In vitro , by inhibiting the expression of NF-κB in BV2 microglia and using Transwell co-culture systems of BV2 microglia and neurons, the effects of APN-P on neuroprotection and the underlying mechanism were investigated. Results In the cortical microglia of 12-week-old CCH rats, the expression of APN protein was significantly downregulated compared to the sham rats. CCH damages neurons and activates cortical microglial polarization to an M1-type by upregulating inflammatory factors. APN-P supplementation upregulated APN expression in cortical microglia, with neuronal survival as well as microglial polarization from an M1 toward an M2 phenotype in CCH cortex. In vivo and in vitro experiments revealed that APN-P promoted the expression of anti-inflammatory factors and neuronal survival by inhibiting NF-κB signaling, thus improving the cognitive function in CCH rats. Conclusions Our study revealed a novel mechanism by which APN-P suppresses the NF-κB pathway and promotes microglial polarization from M1 toward the M2-type to reduce neuron damage in the cortex after CCH.