Inhibition of miR-129 Improves Neuronal Pyroptosis and Cognitive Impairment Through IGF-1/GSK3β Signaling Pathway: An In Vitro and In Vivo Study

Abstract

Pyroptosis is a programmed cell death process which is accompanied by inflammation. The aims of this in vitro and in vivo study were to reveal whether miR-129 contributed to neuronal pyroptosis and cognitive impairment and to further explore its mechanism involved. PC-12 cells were treated with LPS, miR-129 antagomir, AXL1717 (IGF-1 receptor blocker), or SB216763 (GSK3β blocker). After that, expression of miR-129 was measured using qRT-PCR. Relationship between miR-129 and IGF-1 was revealed using luciferase reporter assay. Protein expression of IGF-1, p-Ser9-GSK3β, NLRP3, and Caspase-1 was determined using western blotting. Pyroptosis rate was measured using flow cytometry. Wistar rats were fed with high-fat diet to induce neural inflammation and were further treated with miR-129 antagomir through intracerebroventricular injection. Then, cognitive impairment was assessed by water maze test. Expression of the proteins mentioned above was measured again in midbrain and hippocampus of the rats. In the PC-12 cells, LPS-induced neuronal pyroptosis can be alleviated by miR-129 antagomir. IGF-1 was a specific target for miR-129. Up-regulation and down-regulation of IGF-1/GSK3β signaling pathway separately alleviated and deteriorated neuronal pyroptosis in the cells. In the rats, high-fat diet caused cognitive impairment following with neuronal pyroptosis and down-regulation of IGF-1/GSK3β signaling pathway in midbrain and hippocampus tissues. Also, miR-129 antagomir improved these abnormalities in the rats. Inhibition of miR-129 improved neuronal pyroptosis and cognitive impairment through IGF-1/GSK3β signaling pathway.

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Data Availability

The data cannot be shared due to the fact that this is an ongoing study.

Code Availability

All these analyses were performed using SPSS 18.0 software (US).

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Acknowledgments

We want to thank Prof. JQ from TIANJIN UNIVERSITY (China) for the funding and laboratory support for this project.

Funding

This project is supported by the National Natural Science Fund (81471252; 81772060).

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Correspondence to Feng Wang or Qiang Zhang or Ping Lei.

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The study was approved by the ethics committees of Tianjin Medical University General Hospital and Tianjin Anding Hospital (Tianjin, China).

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Wang, F., Wang, L., Sui, G. et al. Inhibition of miR-129 Improves Neuronal Pyroptosis and Cognitive Impairment Through IGF-1/GSK3β Signaling Pathway: An In Vitro and In Vivo Study. J Mol Neurosci (2021). https://doi.org/10.1007/s12031-021-01794-x

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Keywords

  • Cognitive impairment
  • High-fat diet
  • IGF-1
  • Inflammation
  • MiR-129
  • Pyroptosis