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The Role of Somatostatin in Alzheimers Disease: Modulation of NLRP3-Mediated Microglial Pyroptosis via the MDM2/DPP4/Sirt1 axis
Vol 38, Issue 3, 2024
Abstract
Background: The progression of Alzheimers 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 μM amyloid-β protein fragment 1-42 (Aβ1-42). 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 1β (IL-1β), interleukin 18 (IL-18)) were quantified using enzyme-linked immunosorbent assay, followed by the determination of lactate dehydrogenase (LDH) release. Intracellular Aβ1-42 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-1β and IL-18 levels, LDH release, Aβ1-42 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, Aβ1-42 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.
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Supporting Agencies
Copyright (c) 2024 Yamin Zhang, Jianping Wang, Jin Yuan, Ruipeng Wu, Xiaojuan Hu, Fulin Gao, Yanqing Sun
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Medical Genetics, University of Torino Medical School, Italy

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy