Mir-199a-3p Aggravates Neuroinflammation in an Alzheimer's Disease Transgenic Mouse Model by Promoting M1-Polarization Microglia (PRJCA040334)
Background: One core mechanism of Alzheimer's disease (AD) is chronic neuroinflammation in which M1-polarization microglia plays a key role. Expression of miR-199a-3p and inflammatory factors significantly increased in hippocampal tissues of transgenic AD mouse models and LPS-stimulated BV2 cells. We speculated that miR-199a-3p may aggravates neuroinflammation by promoting M1-Polarization microglia in the progression of AD. Objective: To investigate the effect of miR-199a-3p in the neuroinflammation process leading to AD.Methods: AD mouse model and BV2 cells were used to examine the role of miR-199a-3p in vivo and vitro. Inflammatory cytokines and markers for microglial cell typing were detected. Transcriptome sequencing was performed on miR-199a-3p-modulated BV2 cells, and the sequencing data were cross-analyzed with public databases to predict miR-199a-3p-mediated pathways. Results: Intracerebroventricular injection of miR-199a-3p agomir aggravated amyloid deposition, decreased learning and memory capacity of AD mice, and promoted microglia into M1 phenotype significantly.  Conversely, intracerebroventricular injection of miR-199a-3p antagomir slowed AD progression and inhibited microglia into M1 phenotype. In vitro, miR-199a-3p mimic promoted microglia into M1 phenotype and miR-199a-3p inhibitor inhibited microglia into M1 phenotype in LPS treated BV2 cells. After analyzing sequencing data, we found that miR-199a-3p down-regulated the expression of WDR76, leading to down-regulation of the cell cycle associated pathways, IL-17 pathways and FOXO pathways, resulting in an increase in the proportion of M1 type microglia. Conclusion: MiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings suggests that miR-199a-3p may represent a new therapeutic target for AD.