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

Macarena S. Aloi,Katherine E. Prater,B. Sopher,Stephanie Davidson,S. Jayadev,G. Garden

Published 2021 in Glia

ABSTRACT

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 β‐Amyloid (Aβ) 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 Aβ1‐42 (fAβ1‐42), in vitro. We hypothesized that in microglia, miR‐155 expression would impact the internalization and catabolism of extracellular fAβ1‐42. 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 fAβ1‐42 to low‐pH compartments where catabolism occurs, while miR‐155 overexpression decreases fAβ1‐42 catabolism. Uptake of fAβ1‐42 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 fAβ1‐42 through interconnected mechanisms modulated by miR‐155. Understanding how miRNAs modulate the ability of microglia to catabolize fAβ1‐42 will further elucidate the role of cellular players and molecular crosstalk in AD pathophysiology.

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