中国病理生理杂志2025，Vol.41Issue(6)：1128-1133,6.DOI:10.3969/j.issn.1000-4718.2025.06.009
ZBP1/RIPK1/MLKL通路介导AD小鼠神经元坏死性凋亡的作用研究
Study on role of ZBP1/RIPK1/MLKL pathway in mediating neuronal necroptosis in AD mice
摘要
Abstract
AIM:To investigate the mechanism by which the Z-DNA-binding protein 1(ZBP1)/receptor-in-teracting protein kinase 1(RIPK1)/mixed lineage kinase domain-like protein(MLKL)pathway modulates the necroptosis of neurons in a mouse model of Alzheimer disease(AD).METHODS:Thirty mice were randomly divided into three groups:normal control(NC)group,APP/PS1 model(MOD)group,and necroptosis inhibitor necrostatin-1(Nec-1)group,each with 10 mice.The learning and memory capacities of mice were assessed using the Morris water maze assays.The pathological morphology of hippocampal tissue was examined based on the HE staining assay.The expression levels of tumor necrosis factor-α(TNF-α)and interleukin-10(IL-10)in serum samples were measured by ELISA.The phosphory-lation of amyloid precursor protein(APP),Tau protein and the expression levels of proteins related to the ZBP1/RIPK1/MLKL pathway in hippocampal tissue were measured by Western blot.Immunofluorescence analysis was performed to de-tect the positive expression of p-RIPK1,while the mRNA level of ZBP1 was measured by RT-qPCR.RESULTS:Com-pared with NC group,the escape latency of mice in the MOD group was significantly longer(P<0.05),the number of crossing platforms was reduced(P<0.05),and the arrangement of hippocampal neurons was disordered accompanied with nuclear condensation.The concentration of TNF-α in serum was increased,whereas the concentration level of IL-10 was decreased(P<0.05).The expression levels of APP,p-Ttau and ZBP1 proteins in the hippocampal tissue and the ratios of p-RIPK1/RIPK1,p-RIPK3/RIPK3 and p-MLKL/MLKL were significantly upregulated(P<0.05).Similarly,the positive expression level of p-RIPK1 and the mRNA level of ZBP1 in hippocampal tissue were significantly upregulated(P<0.05).Compared with the MOD group,the cognitive function of AD mice,pathological damage of hippocampal tissue,and the levels of TNF-α and IL-10 in serum were reversed in the Nec-1 group(P<0.05).Moreover,the Nec-1 treatment signifi-cantly downregulated the expression levels of the above proteins(P<0.05),and the positive expression of p-RIPK1 and the mRNA level of ZBP1 were significantly decreased(P<0.05).CONCLUSION:The ZBP1/RIPK1/MLKL pathway is involved in the occurrence of neuronal necroptosis and the pathological process of AD mice.Inhibition of this pathway sig-nificantly ameliorates cognitive dysfunction and neuroinflammatory responses in AD mice.关键词
阿尔茨海默病/坏死性凋亡/ZBP1/RIPK1/MLKL通路Key words
Alzheimer disease/necroptosis/ZBP1/RIPK1/MLKL pathway分类
医药卫生引用本文复制引用
朱小敏,陈炜,符钰岚,卓桂锋,黄颖睿,张颖,吴林..ZBP1/RIPK1/MLKL通路介导AD小鼠神经元坏死性凋亡的作用研究[J].中国病理生理杂志,2025,41(6):1128-1133,6.基金项目
国家自然科学基金资助项目(No.82460906) （No.82460906）
广西中医药大学"岐黄工程"高层次人才团队项目(No.202410) （No.202410）
广西高等学校高水平创新团队及卓越学者计划(桂教人才[2020]6号) （桂教人才[2020]6号）
广西中医药重点学科建设项目(No.GZXK-Z-20-13) （No.GZXK-Z-20-13）
