The pro‐inflammatory microRNA miR‐155 influences fibrillar β‐Amyloid1‐42 catabolism by microglia. Issue 7 (10th March 2021)

• Record Type: Journal Article
• Authors: Aloi, Macarena S.; Prater, Katherine E.; Sopher, Bryce; Davidson, Stephanie; Jayadev, Suman; Garden, Gwenn A.
• Is Part Of: Glia. Volume 69:Issue 7(2021)
• Page Start: 1736
• Page End: 1748
• Publication Date: 2021-03-10
• Subjects: catabolism -- fibrillar Aβ1‐42 -- miR‐146a -- miR‐155 -- miRNAs -- primary microglia; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23988
• Languages: English
• ISSNs: 0894-1491

Abstract

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. Main Points: LPS stimulation leads to fast‐miR‐155 and slow‐miR‐146a upregulation and suppressed fibrillar Aβ catabolism by microglia. Conditional miR‐155 overexpression lowers fibrillar Aβ capacity in the endolysosomal pathway; conditional miR‐155 deletion has the opposite impact.