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miRNA-22 在调控阿尔茨海默病神经炎症中的作用机制。

Mechanism of microRNA-22 in regulating neuroinflammation in Alzheimer's disease.

机构信息

State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing, China.

Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.

出版信息

Brain Behav. 2020 Jun;10(6):e01627. doi: 10.1002/brb3.1627. Epub 2020 Apr 19.

DOI:10.1002/brb3.1627
PMID:32307887
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7303389/
Abstract

BACKGROUND

Study on the expression of miRNA-22 in serum of Alzheimer's disease (AD) patients and the mechanism of neuroinflammation regulation.

METHODS

ELISA 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.

RESULTS

In 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.

CONCLUSION

miRNA-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.

摘要

背景

研究阿尔茨海默病（AD）患者血清中 miRNA-22 的表达及其对神经炎症调节的机制。

方法

采用 ELISA 法检测 AD 患者血清中炎症因子白细胞介素-1β（IL-1β）、白细胞介素-18（IL-18）和肿瘤坏死因子-α的水平。TargetScan 数据库和荧光素酶报告基因检测表明，Gasdermin D（GSDMD）是 miRNA-22 的靶基因。将 miRNA-22 模拟物转染入微胶质细胞，然后用 LPS 和 Nigericin 诱导细胞发生 pyroptosis。

结果

本研究发现，AD 患者外周血中 miRNA-22 的表达水平低于健康人群。AD 患者的炎症因子表达水平高于健康人群，且与 miRNA-22 呈负相关。miRNA-22 模拟物可显著抑制细胞发生 pyroptosis，下调 GSDMD 和 p30-GSDMD 的表达，减少炎症因子的释放，下调 NLRP3 炎症小体的表达作为反馈。在 APP/PS1 双转基因小鼠模型中，注射 miRNA-22 模拟物可显著改善小鼠的记忆能力和行为。此外，下调了小鼠脑组织中 pyroptosis 关键蛋白，包括 GSDMD 和 p30-GSDMD 的表达，同时炎症因子的表达也减少了。

结论

miRNA-22 与 AD 患者炎症因子的表达呈负相关，miRNA-22 可通过靶向 GSDMD 调节胶质细胞的炎症性细胞 pyroptosis 释放，从而改善 AD 小鼠的认知能力。miRNA-22 和 pyroptosis 是治疗 AD 的潜在新靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/212122c5f6ce/BRB3-10-e01627-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/212122c5f6ce/BRB3-10-e01627-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/2acdf5f6a091/BRB3-10-e01627-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/f4e116f3e297/BRB3-10-e01627-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/4aaafe65d811/BRB3-10-e01627-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/9e1e3559c320/BRB3-10-e01627-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/0a039aac8b39/BRB3-10-e01627-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/cabc44c52462/BRB3-10-e01627-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/50bc68acbadb/BRB3-10-e01627-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/7a191ba752c2/BRB3-10-e01627-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e7fb/7303389/212122c5f6ce/BRB3-10-e01627-g002.jpg

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