Abstract
BackgroundStudy on the expression of miRNA‐22 in serum of Alzheimer's disease (AD) patients and the mechanism of neuroinflammation regulation.MethodsELISA assay was used to detect the serum level of inflammatory factors, including interleukin‐1β (IL‐1β), interleukin‐18 (IL‐18), and tumor necrosis factor‐α in AD patients. TargetScan database and luciferase reporter gene assay indicated that gasdermin D (GSDMD) was the target gene of miRNA‐22. miRNA‐22 mimic was transfected into microglia, followed by administration of LPS and Nigericin to induce pyroptosis.ResultsIn this study, we found that the expression level of miRNA‐22 in peripheral blood was lower in AD patients than that in healthy population. The expression of inflammatory factors was higher in AD patients than that in healthy people, which was negatively correlated with miRNA‐22. miRNA‐22 mimic could significantly inhibit pyroptosis, the expression of GSDMD and p30‐GSDMD was down‐regulated, the release of inflammatory factor was decreased, and the expression of NLRP3 inflammasome was down‐regulated as feedback. In the APP/PS1 double transgenic mouse model, the injection of miRNA‐22 mimic significantly improved the memory ability and behavior of mice. In addition, the expression of the vital protein of pyroptosis in mouse brain tissue, including GSDMD and p30‐GSDMD, was down‐regulated, and the expression of inflammatory factors was also decreased.ConclusionmiRNA‐22 was negatively correlated with the expression of inflammatory factors in AD patients, and miRNA‐22 could inhibit the release of inflammatory cytokines by regulating the inflammatory pyroptosis of glial cells via targeting GSDMD, thereby improving cognitive ability in AD mice. miRNA‐22 and pyroptosis are potential novel therapeutic targets in the treatment of AD.
Highlights
Alzheimer's disease (AD) is a chronic neurodegenerative disease, clinically characterized by memory impairment, cognitive impairment, visual spatial ability, and abstract thinking damage (Guerriero, Sgarlata, & Francis, 2016)
The overexpression of gasdermin D (GSDMD) could resist pyroptosis caused by miRNA-22, which was manifested by increased cytotoxicity in the MG + mimic + GV362 group, increased Propidium iodide (PI) uptake, and up-regulated expression of inflammatory factors in the medium
The results of IHC and Western blot showed that the expression of inflammatory factors was down-regulated in mouse hippocampus, and the expression of NLRP3, GSDMD, and p30-GSDMD was simultaneously down-regulated, indicating that miRNA-22 mimic attenuated the activation of NLRP3 inflammasome and the expression of inflammatory factors, thereby inhibiting the overall neuroinflammatory response
Summary
Alzheimer's disease (AD) is a chronic neurodegenerative disease, clinically characterized by memory impairment, cognitive impairment, visual spatial ability, and abstract thinking damage (Guerriero, Sgarlata, & Francis, 2016). MG can clear Aβ by LDL receptor (LRPs)mediated signaling; in the case of AD progression and further aggregation of Aβ, the recognition ability and phagocytic ability of MG are weakened At this point, the massive activation of MG can form a large number of inflammatory factors, including interleukins, such as interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) (KerenShaul et al, 2017; Sarlus & Heneka, 2017). MiRNAs have been found to play important roles in various diseases, and the abnormal expression of a large number of miRNAs has been found in AD studies (Chang, Wang, & Zhu, 2017); the regulation mechanism of miRNAs in AD-related neuroinflammation has rarely been reported. In this study, we explored the regulatory roles and modes of miRNA-22 in AD-related neuroinflammation
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