Silencing of long noncoding RNA X-inactive specific transcript alleviates Aβ1-42-induced microglia-mediated neurotoxicity by shifting microglial M1/M2 polarization

• Published in: International journal of immunopathology and pharmacology 2023-01, Vol.37, p.3946320231184988-3946320231184988
• Main Authors: Zhao, Kun-Peng, Wang, Xin-Yu, Shao, Mei-Qi, He, Chen-Yang, Yuan, Fu-Qiang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Apoptosis; Bioinformatics; Caspase-3; Cell viability; Cytology; DNA nucleotidylexotransferase; Enzyme-linked immunosorbent assay; Immunohistochemistry; Inflammation; Kinases; Mice; Microglia; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Neurodegenerative diseases; Neurotoxicity; Non-coding RNA; Original; Phosphatidylinositol 3-Kinases; Polarization; Presenilin 1; Proto-Oncogene Proteins c-akt - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA-mediated interference; Spatial discrimination learning; Spatial memory
• ISSN: 0394-6320; 2058-7384
• DOI: 10.1177/03946320231184988

Objectives This experimental study aims to investigate the role of long noncoding RNA X-inactive specific transcript (lncRNA XIST) in the microglial polarization and microglia-mediated neurotoxicity in Alzheimer’s disease (AD). Methods The levels of XIST and microRNA-107 (miR-107) were detected by quantitative real-time polymerase chain reaction. The spatial learning and memory capability of APPswe/PS1dE9 (APP/PS1) mice were evaluated by the Morris water maze test. The morphology of mouse hippocampus cells was evaluated by hematoxylin and eosin staining. The Iba1-positive microglia were labeled by immunohistochemistry staining. The protein levels were determined by western blot and enzyme-linked immunosorbent assay. Neurotoxicity was evaluated by the terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, caspase-3 activity, and Cell Counting Kit-8 assay. The XIST, miR-107, and AD targets were predicted by bioinformatics analysis. Results The level of XIST was increased in APP/PS1 mice, and XIST silencing ameliorated AD progression. XIST silencing suppressed microglia activation, microglial M1 polarization, and proinflammatory factor levels, but promoted microglial M2 polarization in APP/PS1 mice and Aβ1-42-treated BV-2 cells. XIST knockdown reduced Aβ1-42-induced microglia-mediated apoptosis and enhanced cell viability in HT22 cells. XIST silencing down-regulated miR-107 level and attenuated Aβ1-42-caused suppression of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Those effects of XIST silencing were attenuated by miR-107 inhibitor or LY294002. Conclusion Downregulation of XIST lessened Aβ1-42-induced microglia-mediated neurotoxicity by modulating microglial M1/M2 polarization, which may be mediated by the miR-107/PI3K/Akt pathway.