摘要： Objective：During normal aging，innate immunity progresses to a chronic state. However，how oxidative stress and chronic neuroinflammation arise during aging remain unclear. In this study，we intended to demonstrate the novel function of Cathepsin B （CatB） in the age related oxidative stress and chronic neuroinfl ammation. Methods：①2 month-old and 20 month-old wild-type and CatB-/- mice were used for learning and memory tests by step through passive avoidance tests. The cumulative potentiation of the fi eld excitatory postsynaptic potential（ fEPSP） slope and dendritic spine density were also examined. ②Infl ammation were examined by immunoblotting of interleukin-1β（ IL-1β），tumor necrosis factor-α（ TNF-α） and inducible nitric oxide synthase（ iNOS），and oxidative stress were examined by checking the level of 8-oxo-7，8-dihydro-2’-deoxyguanosine （8-oxo-dG） and 4-hydroxynonenal（ 4-HNE） in the hippocampal lysate of 2 month-old and 20 month-old wild-type and CatB-/- mice. ③Intra-lateral ventricle transplantation of CatB over-expressed microglia in middleaged mice，learning and memory were examined by Y-maze and novel objective tests. Results：①The retention latencies of both aged groups were significantly longer than those in the acquisition trial. The retention latency of four consecutive trials was signifi cantly longer in aged CatB-/- mice than in aged wild-type mice. Furthermore，the mean relative fEPSP slope measured at 30 min after stimulation with 25，50 and 100 Hz in the aged CatB-/- mice was significantly larger than that in the aged wildtype mice. The mean dendritic spine density of CA1 neurons in the aged CatB-/- mice was signifi cantly
larger than that in the aged wild-type mice. ②The mean levels of CatB，iNOS，IL-1β and TNF-α in the hippocampus were signifi cantly higher in aged wild-type mice than in younger animals. Furthermore， their mean levels in the hippocampus of aged CatB-/- mice were significantly lower than those in aged wild-type mice. The mean amounts of these oxidative markers were significantly larger in the hippocampus of aged wild-type mice than in younger animals. The mean relative amount of 8-oxodG and 4-HNE was significantly lower in aged CatB-/- mice than in aged wild-type mice. ③Double immunohistochemical staining was conducted to identify the possible cellular origin of oxidative stress. In the hippocampus of aged wild-type mice，the immunoreactivities of both 8-oxo-dG and 4-HNE were found exclusively in microglia with activated morphology，but not in astrocytes or neurons. ④Intralateral ventricle transplantation of CatB over-expressed microglia signifi cantly impaired the learning and memory in the middle-aged mice. Conclusion：CatB plays a critical role in the mitochondriaderived ROS generation and infl ammatory response，resulting in impairment of learning and memory during normal aging.