Impact of systemic inflammation on neuroinflammation, cognitive functions and phosphorylation of tau by laparotomy. Implication of postoperative cognitive dysfunctions to Alzheimer’s dementia

Abstract

Aims: Systemic inflammation triggered by infection or surgery can stimulate neuroinflammation, and thereby disturbing cognitive functions and even developing Alzheimer’s dementia. We have recently adopted laparotomy surgery as an experimental model for postoperative cognitive dysfunctions (POCD). We aimed to investigate the temporal profile of systemic inflammation, neuroinflammation and cognitive functions for 2 weeks, which has high implication in the development of Alzheimer’s dementia. Method: Adult male wild type C57BL/6N mice (3-month-old) were used for 2 series of experiments. Mice were divided into 3 groups: Control (CON), sevoflurane only (SEVO) and Laparotomy under (LAP). Cognitive function was assessed by Y-maze and Novel Objective Recognition test (NOR). Inflammatory cytokine mRNA expression in liver, frontal cortex and hippocampus were assessed by q-PCR; protein levels in brain tissues and plasma were determined by MILIPLEX assay. Results: There were significantly greater number of errors and longer latency in LAP compared with SEVO in Y-maze test; and higher discrimination index in NOR. Neuroinflammation was found by an increase in IL-1β and IL-6 in the frontal cortex, and IL-1β and IL-8 in the hippocampus. Immunoreactivity of GFAP-labeled astrocytes was higher in LAP in the frontal cortex and activated microglia (Iba1 immunoreactivity) were found in both brain regions. Increased phosphorylation of tau was detected in both brain regions in LAP at 14d. Neuro- and peripheral inflammation and tau protein phosphorylation were reversed by ibuprofen, and cognition deficits were improved as well. Conclusion: Neuroinflammation induced by laparotomy activates astrocytes and microglia, increases tau phosphorylation that finally impaired the cognition.