The pro-inflammatory microRNA miR-155 influences fibrillar β-Amyloid1-42 catabolism by microglia

Microglia are the innate immune cells of the central nervous system that adopt rapid functional changes in response to Damage Associated Molecular Patterns, including aggregated beta-Amyloid (A beta) found in Alzheimer's disease (AD). microRNAs (miRNAs) are post-transcriptional modulators that influence the timing and magnitude of microglia inflammatory responses by downregulating the expression of inflammatory effectors. Recent studies implicate miR-155, a miRNA known to regulate inflammatory responses, in the pathogenesis of neurodegenerative disorders including multiple sclerosis, ALS, familial Parkinson's disease, and AD. In this work, we asked if miR-155 expression in microglia modifies cellular behaviors in response to fibrillar A beta(1-42) (fA beta(1-42)), in vitro. We hypothesized that in microglia, miR-155 expression would impact the internalization and catabolism of extracellular fA beta(1-42). Primary microglia stimulated with lipopolysaccharide demonstrate fast upregulation of miR-155 followed by delayed upregulation of miR-146a, an anti-inflammatory miRNA. Conditional overexpression of miR-155 in microglia resulted in significant upregulation of miR-146a. Conditional deletion of miR-155 promoted transit of fA beta(1-42) to low-pH compartments where catabolism occurs, while miR-155 overexpression decreases fA beta(1-42) catabolism. Uptake of fA beta(1-42) across the plasma membrane increased with both up and downregulation of miR-155 expression. Taken together, our results support the hypothesis that inflammatory signaling influences the ability of microglia to catabolize fA beta(1-42) through interconnected mechanisms modulated by miR-155. Understanding how miRNAs modulate the ability of microglia to catabolize fA beta(1-42) will further elucidate the role of cellular players and molecular crosstalk in AD pathophysiology.

Automated summary

Microglia play a crucial role in neurodegenerative diseases by modulating inflammatory responses through miR-155, affecting the cellular ability to degrade Aβ.