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

B01.c. Disease Mechanisms, Pathophysiology: Inflammation - no. ADPD7-0595Aims: 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

Altered dendritic spine plasticity in a mouse depression model

Conference Theme: Nature and Nurture in Brain FunctionsDepressive disorder is a most prevalent psychiatric disorder worldwide and is estimated to be affecting 350 millions of the global population. In the prefrontal cortex (PFC) of depression patients, hypofunction is accompanied with structural deficits, including decreased cell number, neuronal atrophy and decreased number of spine synapses. In rodents, chronic stress exposure induces depressive-like behaviour and results in structural impairment of dendrites of layer 2/3 and 5 pyramidal neurons in PFC, including reduced dendritic spine density and atrophy of apical dendrites. However, it is unclear whether dendritic deficits contribute to depression development. Ketamine, a NMDA receptor blocker, is found to exert rapid, lasting antidepressant effect at a single, sub-anaesthetic dose. Ketamine can also rapidly reverse chronic stress-induced synaptic deficit. Yet, data on the effect of ketamine on dendritic spine plasticity in long-term is lacking. In this study, we used in vivo two-photon transcranial imaging of Thy1-YFP H line mice to investigate dendritic spine plasticity in the chronic restraint stress (CRS) depression model. We found that CRS increased dendritic spine elimination and reduced spine formation of layer V pyramidal neurons in the frontal association cortex. In addition, CRS-induced alterations in spine plasticity precede the onset of behavioural symptoms. Importantly, we found that ketamine treatment counteracted the effects of stress on dendritic spine plasticity. REFERENCES: 1. Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. Science, 338(6103), 68-72. 2. Licznerski, P., & Duman, R. S. (2013). Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression. Neuroscience, 251, 33-50

The relationship between tau protein phosphorylation and surgical trauma in post operative cognitive dysfunction

Conference Theme: Science and Aging: An Era of Discover

Differential inflammatory effects in the brain and post operative cognitive performance from surgical trauma when compared with anaesthesia exposure without surgery

Session 01AP06: Abstract Presentation Session - Anaesthesia and Immune-Modulation: no. 01AP06-2Background and Goal of Study: Postoperative cognitive dysfunction (POCD) is associated with abnormal tau protein phosphorylation and neuroinflammation, findings commonly seen with Alzheimer’s Disease1,2 This study investigates the contribution of surgical trauma as compare with anaesthesia exposure alone to the development of this condition. Materials and methods: Young wild type C57BL/6N mice were divided into control (CON) sevoflurane only (SEVO) and laparotomy (LAP) groups. Cognitive function was assessed by Y-maze analysis 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. 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. Results and discussion: No dif ferences were seen for locomotor activity but 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. Hepatic mRNA levels of IL-1β, TNF-α, IL-8 and MCP-1 were significantly increased at 4h in LAP compared with SEVO and CON. 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 DG region of hippocampus. There were also more activated microglia (IBA-1 labeled) in CA1 and DG regions of the hippocampus. These results indicate that both peripheral and neuroinflammation and astrocytes and microglia activation are more pronounced following trauma compared with sevoflurane exposure alone and this corresponds to delayed cognitive impairment. Conclusion(s): These data further support that POCD is a condition that is more related to surgical trauma than to anaesthesia exposure. References: 1. Iqbal, K., et al Curr Alzheimer Res, 2010. 7(8): p. 656-64. 2. Run, X., et al J Alzheimers Dis, 2010. 22 Suppl 3: p. 49-55. 3. Wan, Y., et al Anesthesiology, 2007. 106(3): p. 436-43. Acknowledgements: This work is supported in part by the HK

Effects of Lycium barbarum on modulation of blood vessel and hemodynamics

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

Conference Theme: Nature and Nurture in Brain FunctionsOBJECTIVES: 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