上下两济丹调控NLRP3/Caspase-1/GSDMD通路改善AD小鼠学习记忆能力及神经损伤的机制研究OA

Objective To investigate the improving effects of Shangxia Liangji Pill(上 下 两 济 丹,SXLJP)on learning and memory ability and neuro injury in APP/PS1 mice,and clarify whether it acts by regulating the NLRP3/Caspase-1/GSDMD pathway.Methods APP/PS1 mice served as the Alzheimer's disease(AD)model and were assigned to the control group,model group,low/middle/high-dose SXLJP groups,and donepezil hydrochloride group.After administration,novel object recognition test and Morris water maze test were used to assess learning and memory;Nissl and Golgi staining were performed to observe hippocampal neuronal and synaptic structures;Thioflavin S staining detected Aβ deposition;immunofluorescence and Western blot(WB)were used to measure the expression of neuroinflammatory indicators and pathway proteins.Results Compared with the model group,each dose of SXLJP significantly increased the novel object recognition index(P＜0.05),shortened the escape latency and distance to the platform in the Morris water maze,and increased the target quadrant residence time and platform crossings(P＜0.05 or P＜0.01).Nissl staining showed increased neuronal density and improved structural integrity in the hippocampal CA3 region(P＜0.05 or P＜0.01);Golgi staining and WB confirmed enhanced dendritic spine density and expression of PSD95 and SYN proteins,thus amelio-rating synaptic damage(P＜0.05 or P＜0.01).Additionally,it reduced hippocampal Aβ deposition(P＜0.05 or P＜0.01),down-regulated Iba1,CD86,IL-1β and TNF-α expression(P＜0.05),inhibited NLRP3,Caspase-1 and GSDMD-N protein expression.Conclusion SXLJP could ameliorate learning and memory impairment,alleviates neuronal/synaptic damage and Aβ deposition in APP/PS1 mice,with its mechanism possibly involving inhibiting neuroinflammation and regulating the NLRP3/Caspase-1/GSDMD pathway.