Mir-711 Differentially Regulates Early And Sustained aβ42o-induced

Neuroinflammation In Microglia

 

Background: Neuroinflammation is a central driver of Alzheimer’s disease (AD) progression

and is mainly mediated by microglial activation. Activation of Toll-like receptor 4 (TLR4) by

Aβ species initiates MYD88-dependent NF-κB signaling and NLRP3 inflammasome priming,

leading to release of pro-inflammatory cytokines. MicroRNAs (miRNAs) have emerged as

critical post-transcriptional regulators of microglial immune responses, and miR-711 has

attracted attention for its modulation of inflammation. However, the role of miR-711, which

targets TLR4, in Aβ42o-induced neuroinflammation remains poorly defined.

 

Methods: Human microglial HMC3 cells were stimulated with Aβ1-42 oligomers (Aβ42o) to

establish an i n vi t r o neuroinflammatory model at early (6 h) and prolonged (24 h) time

points. miR-711 expression and the TLR4/MYD88/NF-κB/NLRP3/CASP1 signaling axis were

evaluated using qRT-PCR, Western blotting, ELISA, and viability assays. The regulatory impact

of miR-711 on microglial activation was assessed using gain- and loss-of-function

approaches. Statistical analyses were performed using Student’s t-test for comparisons

between two groups and one-way or two-way ANOVA for comparisons involving more than

two groups. A p-value < 0.05 was considered statistically significant.

 

Results: Aβ42o stimulation significantly downregulated miR-711 expression while

upregulating TLR4/NF-κB/NLRP3 signaling and pro-inflammatory cytokine release.

Overexpression of miR-711 markedly suppressed TLR4 (p<0.0001), NF-κB (p<0.0001), and

NLRP3 (p<0.001) expression levels, reduced IL-1β secretion (p<0.05), while rescuing cell

viability by approximately 15% during early Aβ42o exposure (p<0.001). However, MYD88 and

CASP1 expression levels were exacerbated (p<0.001; p<0.0001, respectively), and cytokine

release was enhanced after miR-711 inhibition. Conversely, prolonged Aβ42o exposure

resulted in partial reactivation of inflammatory signaling despite miR-711 overexpression,

characterized by increased MYD88 (p<0.001), NLRP3 (p <0.01), and NF-κB (p<0.05)

expression, while TLR4 (p < 0.0001) and CASP1 (ns) remained suppressed.

 

Conclusion: miR-711 functions as a dynamic molecular brake that attenuates early microglial

activation while allowing partial immune adaptation during sustained Aβ42o exposure. These

findings position miR-711 as a promising therapeutic target for limiting acute

neuroinflammation while highlighting compensatory late-phase signaling that may limit the

durability of its protective effects. Time-dependent miR-711-based interventions could be

investigated to refine therapeutic strategies mitigating microglial-driven neuroinflammation.