文献类型：期刊文献

英文题名：The Role of Somatostatin in Alzheimer's Disease: Modulation of NLRP3-Mediated Microglial Pyroptosis via the MDM2/DPP4/Sirt1 axis

作者：Zhang, Yamin[1,2];Wang, Jianping[3];Yuan, Jin[1];Wu, Ruipeng[2];Hu, Xiaojuan[2];Gao, Fulin[2];Sun, Yanqing[4]

第一作者：张艺梦;Zhang, Yamin

通信作者：Sun, YQ[1]

机构：[1]Gansu Univ Chinese Med, Lanzhou 730000, Gansu, Peoples R China;[2]Gansu Prov Hosp, Dept Neurol, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Prov Hosp, Dept Emergency, Lanzhou 730046, Gansu, Peoples R China;[4]Gansu Prov Hosp, Dept Clin Teaching, Lanzhou 730000, Gansu, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Prov Hosp, Dept Clin Teaching, Lanzhou 730000, Gansu, Peoples R China.

年份：2024

卷号：38

期号：3

起止页码：2181

外文期刊名：JOURNAL OF BIOLOGICAL REGULATORS AND HOMEOSTATIC AGENTS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001184305100001)】；

基金：This work was supported by Natural Science Foun-dation of Gansu Province [Grant Number: 22JR5RA679] , Gansu Provincial Hospital Cultivation Project [Grant Num-ber: ZX-62000001-2022-169] and Gansu Provincial Hos-pital Science and Technology Innovation Platform Project [Grant Number: ZX-62000001-2021-210] .

语种：英文

外文关键词：Alzheimer's disease; NOD-like receptor family protein 3; somatostatin; sirtuin 1

摘要：Background: The progression of Alzheimer's disease (AD) is closely linked to microglial pyroptosis. This study investigated the impact of somatostatin (SST) on microglial pyroptosis in AD and elucidated the underlying mechanisms. Methods: In -vitro AD cell models were established through sequential stimulation with 100 ng/mL lipopolysaccharide and 10 mu M amyloid-beta protein fragment 1-42 (A beta 1-42). The model cells which were transfected with or without silencing transformed mouse 3T3 cell murine double minute 2 (MDM2) or/and sirtuin 1 (Sirt1) overexpression plasmid, underwent SST treatment. Pro-inflammatory cytokines (interleukin 1 beta (IL-1 beta), interleukin 18 (IL -18)) were quantified using enzyme-linked immunosorbent assay, followed by the determination of lactate dehydrogenase (LDH) release. Intracellular A beta 1-42 deposition, NOD -like receptor family protein 3 (NLRP3)-mediated pyroptosis, and the MDM2/dipeptidyl peptidase 4 (DPP4)/Sirt1 axis were assessed using propidium iodide staining, immunofluorescence staining, and Western blot. The interaction between MDM2 and DPP4 was validated through ubiquitination analysis. Results: SST upregulated MDM2 and Sirt1 levels, leading to MDM2 ubiquitination and subsequent degradation of DPP4 in BV2 cells. Moreover, SST downregulated IL-1 beta and IL -18 levels, LDH release, A beta 1-42 deposition, and the expressions of DPP4, NLRP3, N-gasdermin D (N-GSDMD), and caspase-1 in AD model cells (p < 0.001). These effects were reversed by MDM2 silencing (p < 0.001). However, Sirt1 overexpression counteracted the effects of MDM2 silencing on SST-treated model cells by reducing pro-inflammatory cytokine production, LDH release, A beta 1-42 deposition, and NLRP3-mediated pyroptosis (p < 0.001). Conclusion: SST activates the MDM2/DPP4/Sirt1 axis to inhibit NLRP3-mediated microglial pyroptosis and thereby alleviates AD. This discovery presents a promising strategy for AD therapy.