The miR-25802/KLF4/NF-κB signaling axis regulates microglia-mediated neuroinflammation in Alzheimer’s disease

Feb 15, 2024Brain, behavior, and immunity

The miR-25802/KLF4/NF-κB pathway controls microglia-driven brain inflammation in Alzheimer's disease

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Abstract

The novel microRNA miR-25802 may influence Alzheimer's disease progression.

miR-25802 levels were higher in the plasma of Alzheimer's patients and in the brains of specific mouse models of the disease.
Increasing miR-25802 levels could worsen symptoms like cognitive decline and neuroinflammation, while reducing it may improve these conditions.
miR-25802 appears to work by binding to KLF4 mRNA, which may lead to a shift in microglia toward a pro-inflammatory state.
Inhibition of miR-25802 may enhance anti-inflammatory activity in microglia and reduce inflammation in Alzheimer's mouse models.
Manipulating miR-25802 levels could reverse Alzheimer's-related changes through effects on KLF4 and NF-κB signaling pathways.

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Microglia-mediated neuroinflammation plays a critical role in the occurrence and progression of Alzheimer's disease (AD). In recent years, studies have increasingly explored microRNAs as biomarkers and treatment interventions for AD. This study identified a novel microRNA termed miR-25802 from our high-throughput sequencing dataset of an AD model and explored its role and the underlying mechanism. The results confirmed the miRNA properties of miR-25802 based on bioinformatics and experimental verification. Expression of miR-25802 was increased in the plasma of AD patients and in the hippocampus of APP/PS1 and 5 × FAD mice carrying two and five familial AD gene mutations. Functional studies suggested that overexpression or inhibition of miR-25802 respectively aggravated or ameliorated AD-related pathology, including cognitive disability, Aβ deposition, microglial pro-inflammatory phenotype activation, and neuroinflammation, in 5 × FAD mice and homeostatic or LPS/IFN-γ-stimulated EOC20 microglia. Mechanistically, miR-25802 negatively regulates KLF4 by directly binding to KLF4 mRNA, thus stimulating microglia polarization toward the pro-inflammatory M1 phenotype by promoting the NF-κB-mediated inflammatory response. The results also showed that inhibition of miR-25802 increased microglial anti-inflammatory M2 phenotype activity and suppressed NF-κB-mediated inflammatory reactions in the brains of 5 × FAD mice, while overexpression of miR-25802 exacerbated microglial pro-inflammatory M1 activity by enhancing NF-κB pathways. Of note, AD-associated manifestations induced by inhibition or overexpression of miR-25802 via the NF-κB signaling pathway were reversed by KLF4 silencing or upregulation. Collectively, these results provide the first evidence that miR-25802 is a regulator of microglial activity and establish the role of miR-25802/KLF4/NF-κB signaling in microglia-mediated neuroinflammation, suggesting potential therapeutic targets for AD.

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