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Mir-199a-3p aggravates neuroinflammation in an Alzheimer's disease transgenic mouse model by promoting
Chenyang Wang1, Xiaolu Bu2, Mengyao Cao2
1Department of Geriatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P.R. China.
Background:
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.
Insights
MicroRNA-199a-3p (miR-199a-3p) promotes M1 microglial polarization, worsening Alzheimer's disease (AD) neuroinflammation and cognitive decline. Targeting miR-199a-3p offers a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Chronic neuroinflammation, driven by M1-polarized microglia, is central to Alzheimer's disease (AD) pathology.
- Elevated miR-199a-3p and pro-inflammatory cytokines are observed in AD models.
- This study investigates the role of miR-199a-3p in exacerbating neuroinflammation via M1 microglial polarization in AD.
Purpose of the Study:
- To explore the function of miR-199a-3p in Alzheimer's disease-associated neuroinflammation.
- To determine if miR-199a-3p promotes M1 microglial polarization in AD progression.
Main Methods:
- Utilized AD transgenic (APPswe/PSEN1dE9) mice and LPS-treated BV2 microglial cells for in vivo and in vitro assessments.
- Measured inflammatory cytokines and microglial cell typing markers.
- Performed transcriptome sequencing and cross-analyzed data with public databases to identify miR-199a-3p-mediated pathways.
Main Results:
- Intracerebroventricular miR-199a-3p agomir administration worsened amyloid deposition, impaired cognition, and promoted M1 microglial polarization in AD mice.
- miR-199a-3p antagomir treatment attenuated AD pathology and suppressed M1 polarization.
- In vitro, miR-199a-3p mimics enhanced M1 polarization, while inhibitors reversed this effect, linked to downregulation of WDR76 and modulation of cell cycle, IL-17, and FOXO pathways.
Conclusions:
- MiR-199a-3p aggravates Alzheimer's disease neuroinflammation by promoting M1-polarized microglia.
- These findings identify miR-199a-3p as a potential therapeutic target for AD treatment.
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