The Impact Of Differentiated Expression Of Microglial Cathepsin C On LPS-mediated Learning And Memory Dysfunction In Mice

Objective:It is known that neuroinflammation in central nervous system (CNS) is involved in pathological processes of many disorders associated with learning and memory dysfunction such as Alzheimer’s disease (AD),vascular dementia (VD),subcortical arteriosclerotic encephalopathy (SAE) and postoperative cognitive dysfunction (POCD).However,the mechanisms of neuroinflammation involved in learning and memory impairment remains unclear. Previously,we found increased expression and enzyme activity cathepsin C(cat C) in microglia in lipopolysaccharide (LPS)-mediated neuroinflammatory mice,but the function of cat C is unknown. The purpose of this study is to clarify the impacts of microglial cathepsin C on LPS-mediated neuroinflammation and on learning and memory dysfunction in mice.Methods:In this study,C57BL/6J mice with genotypes of wild-type (WT),cat C knock down (KD) and cat C over-expression (OE) were intraperitoneally injected with low doses of LPS (100 u g/kg) respectively. Before and 28 hours after injection,Morris water maze was used to test the learning and memory function in mice: Immunohistochemical staining of Iba-1,was used to observe the activation of microglia in the brain:The enzyme-linked immunosorbent method (ELIS A) method was used to detect the expression of inflammatory cytokines(TNF-α and IL-1β) in serum and the brain. Repeated measures multivariate ANOVA and one-way ANOVA were performed for statistical analysis of the data.Results:Twenty-eight hours after LPS intraperitoneal injection,the behavioral test of the water maze showed that cat C OE mice appeared learning and memory dysfunction,while WT and cat C KD mice did not show significant learning and memory dysfunction:Iba-1 immunohistochemical staining showed that microglia in cerebral cortex and hippocampus were activated and the expression of inflammatory cytokines(TNF-β and IL-1β) in serum and the brain were in WT,OE and KD mice following LPS injection. Among them, the changes of OE mice were more significantly higher than WT mice, while the changes of KD mice were more significantly lower than WT mice,.Conclusions:Microglial cathepsin C over-expression promoted LPS mediated production of inflammatory cytokines in serum and the brain,induced activation of microglia in the brain,and aggravated brain neuroinflammation,which may contribute to occurrence of spatial learning and memory deficits in neuroinflammatory mice.