Abstract
Chronic neuroinflammation, driven by M1-polarized microglia, is a core pathological mechanism of Alzheimer's disease (AD). Elevated expression levels of miR-199a-3p and pro-inflammatory cytokines were detected in the hippocampi of AD transgenic mice and in LPS-stimulated BV2 microglial cells. We hypothesized that miR-199a-3p exacerbates neuroinflammation by promoting M1 microglial polarization in AD progression. M1 （AD） 。 AD LPS BV2 miR-199a-3p 。 miR-199a-3p AD M1 。 OBJECTIVE: To explore the role of miR-199a-3p in AD-associated neuroinflammation. miR-199a-3p AD 。 METHODS: AD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 cells were used to assess miR-199a-3p effects in vivo and in 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.AD （APPswe/PSEN1dE9） LPS BV2 miR-199a-3p 。。 miR-199a-3p BV2 ，， miR-199a-3p 。 RESULTS: Intracerebroventricular administration of miR-199a-3p agomir exacerbated amyloid deposition and impaired cognitive function in AD mice, and promoted microglial polarization toward the M1 phenotype. Conversely, treatment with miR-199a-3p antagomir attenuated AD pathology and suppressed M1 polarization. In LPS treated BV2 cells, miR-199a-3p mimics promoted M1 polarization, while inhibitors reversed this effect. Transcriptome analysis revealed that miR-199a-3p downregulated WDR76, subsequently suppressing cell cycle-associated pathways, IL-17 signaling, and FOXO pathways, resulting in an increase in the proportion of M1 type microglia. miR-199a-3p agomir AD ， M1 。， miR-199a-3p AD M1 。 LPS BV2 ，miR-199a-3p M1 ，。，miR-199a-3p WDR76，、 IL-17 FOXO ， M1 。 CONCLUSION: MiR-199a-3p aggravates neuroinflammation of AD by promoting M1-polarization microglia. These findings highlight miR-199a-3p as a potential therapeutic target for AD.