HSP90/MLKL/PGAM5/DRP1通路调控线粒体动力学抗VaD的作用研究OA

Objective:To explore the neuroprotective mechanism of the HSP90/MLKL/PGAM5/DRP1 pathway in vascular dementia(VaD)by regulating the balance of mitochondrial dynamics.Methods:SD rats were randomly divided into sham opera-tion control group,model group and HSP90 inhibitor intervention group by random number table method,with 9 rats in each group.The spatial learning and memory ability of rats was evaluated by the Morris water maze positioning navigation test system.The morphological changes of neurons in the hippocampal CA1 area were observed by combining H&E staining technology.Se-rum Tumor Necrosis Factor-α(TNF-α)was applied by ELISA.The levels of TNF-α and Interleukin-10(IL-10).Western blot was used to detect the expressions of proteins related to the HSP90/MLKL/PGAM5/DRP1 pathway,ATP synthase α subunit(ATP5A),fusion protein 1(MFN1),and fusion protein2(MFN2)in hippocampal tissues.Immunohistochemistry was used to detect the positive expression of p-MLKL.Results:Compared to the sham operation group,the escape latency of rats in the mod-el group was significantly prolonged,the number of crossing platforms was significantly reduced,and obvious neuronal damage was shown in the hippocampal tissue.The level of serum TNF-α increased and the level of IL-10 decreased(P<0.05);The pro-tein levels of HSP90 and PGAM5,the ratio of p-MLKL/MLKL,and the ratio of p-DRP1(ser616)/DRP1 in hippocampal tissue increased,while the protein levels of ATP5A,MFN1,and MFN2 decreased.Meanwhile,the number of P-MLKL positive cells increased significantly(P<0.05).After intervention with HSP90 inhibitors,all the above indicators could be significantly reversed(P<0.05),the pathological damage of hippocampal tissue was alleviated,and the learning and memory abilities were significantly improved.Conclusion:By inhibiting the HSP90/MLKL/PGAM5/DRP1 signaling pathway,it can reduce mitochondrial hyperdi-vision in VaD rats,maintain mitochondrial dynamic balance,inhibit neuroinflammation and improve cognitive function,providing a new target for the treatment of VaD.