The role of TAU protein and inflammation within cognitive dysfunction induced by laparotomy in young animal

Abstract

OBJECTIVES: Postoperative cognitive dysfunction (POCD) is characterized by impairment of memory, concentration, language comprehension, social integration and learning difficulties after surgery. Abnormal tau protein phosphorylation is known to be associated with this disorder and more commonly with Alzheimer’s Disease. This study investigates the contribution of surgical trauma as compared with anaesthesia exposure alone to the development of this condition. METHODS: Adult wild type C57BL/6N male mice (3-month-old, 25 ± 2 g) were divided into control (CON), sevoflurane only (SEVO) and laparotomy (LAP) groups. Cognitive function was assessed by Y-maze analysis and Novel Objective Recognition test (NOR), and locomotor activity by the Open Field test on postoperative day 14. Inflammatory cytokine mRNA expression from the liver, frontal cortex and hippocampus were assessed by q-PCR at 4h and 24h postoperatively. Brain tissues were collected for Western-Blot analysis and immunoflurescent staining. Normalized band intensities were analyzed by One-Way ANOVA followed by Turkey’s post hoc test. All data were expressed as mean ± standard derivation (SD), and p < 0.05 was considered as statistically significant. RESULTS: No difference in the frequency of crossing the square and central duration was seen between groups. Latency and error number were significantly increased in LAP compared with SEVO (n=10-11, p < 0.01 and p < 0.05 respectively) in Y-maze test; the discrimination index in NOR was significantly lower in LAP compared with SEVO (n=7-10, p < 0.001). Hepatic mRNA levels of IL-1β, TNF-α, IL-8 and MCP-1 were significantly increased at 4h in LAP compared with SEVO. IL-1β was elevated in the frontal cortex, as was IL-8 in the hippocampus at 4h in LAP (n= 6-8, p < 0.05). Immunoflurescent positive intensity of GFAP labeled astrocyte was higher in LAP compared with SEVO at the CA1 region of hippocampus. There were also more activated microglia (IBA-1 labeled) in CA1 and DG regions in hippocampus. There was a significant reduction of phosphorylated tau (S396, T205, S404, and AT180) in both SEVO and LAP at 24 h, with no difference between them. However, significantly hyperphosphorylation of tau protein was then in the frontal cortex and hippocampus of LAP at 14d. CONCLUDING REMARKS: Neuroinflammation induced by laparotomy activates astrocytes and microglia, increases tau hyperphosphorylation that finally impaired the cognition with long-term effect. The study is supported by Seed Funding for Basic Research 201311159069 and 201311159171.