Legumain acts on neuroinflammatory to affect CUS-induced cognitive impairment

Cognitive impairment has been widely recognized as a central feature of depression. Legumain, a lysosomal cysteine protease, plays an important role in cancer, atherosclerosis, inflammation and other pathological conditions. Meanwhile, it has been reported that the activation of legumain aggravates the cognitive impairment in neurodegenerative diseases. In this study, we explored the role of legumain in cognitive impairment of stressed mice. Legumain knockout (legumain KO) and wildtype (WT) mice were divided into four groups: control group, chronic mild unpredictable stressed (CUS) group, legumain KO group and legumain KO + CUS group. Our results demonstrated that CUS (4 weeks) induced cognitive impairment in mice effectively based on Morris water maze (MWM) test and novel object recognition (NOR) test and decreased the synaptic plasticity. Additionally, CUS exposure significantly decreased the expression of hippocampal synapse related proteins and the cell density in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines and promoting the activation of microglia in the hippocampus. Legumain KO distinctly restored the CUS-induced negative effects on the indicators mentioned above. In conclusion, our results suggested that legumain may be an effective therapeutic target for cognitive impairment as was seen within the CUS model and legumain KO reduced the level of neuroinflammation, thereby improving the hippocampal synaptic plasticity and cognitive impairment of stressed mice.