The pro‐inflammatory microRNA miR‐155 influences fibrillar β‐Amyloid_1‐42 catabolism by microglia

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.

Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures

“…In addition, in this work, we demonstrate a reduction of insoluble Aβ 1–42 and plaque pathology after miR-155 deletion in microglia. Our work supports previous findings of a role for miR-155 in modulating catabolism of Aβ both in vitro [ 28 ] and now, in vivo. Our study clearly shows that inflammatory miR-155 modulation of microglia functions is pivotal in AD pathophysiology, and that a more nuanced role for miRNA regulation in microglia impacts synapse engulfment and excitability in early pathogenesis.…”

“…We previously reported that conditional knock-out of miR-155 in cultured neonatal microglia led to increased catabolism of fibrillar forms of Aβ 1–42 [ 28 ] . In the APP/PS1 mouse, we observed that conditional knock-out of miR-155 in microglia resulted in upregulation of several anti-inflammatory miR-155 target mRNAs, including a novel putative target, Tfeb .…”

“…More recently, the transcriptional signature of Aβ-plaque associated microglia has revealed significant differences in inflammatory regulation and transcriptional signatures associated with accelerated ageing [ 56 ], and therefore, we focused the role of inflammatory miRNAs, like miR-155, in AD pathogenesis. We observed that inducible loss of miR-155 in primary microglia in vitro resulted in increased catabolism of Aβ 1–42 while overexpression of miR-155 led significantly reduced catabolism [ 28 ]. In the APP/PS1 mouse we observed a significant reduction in cortical insoluble Aβ 1–42 and total plaque load in mice after miR-155 loss in APP/PS1 mice relative to vehicle controls.…”

“…Interestingly, constitutive deletion of miR-155 in both microglia and macrophages did not show alterations in overall survival of the APP/PS1 line, suggesting compensatory mechanisms at play to circumvent the loss of miR-155. Therefore, microglia functions in response to amyloid are regulated by miR-155 (e.g., phagocytosis) [ 28 ] and contribute to circuitry vulnerability and seizures in AD pathophysiology.…”

“…Furthermore, miR-155 targets mRNAs coding for additional molecules involved in suppressing the inflammatory response including, SHIP1 [ 26 ] and SOCS1 [ 27 ], leading to increased pro-inflammatory gene expression. Recently, we identified a novel role for miR-155 in primary microglia, where conditional expression of miR-155 resulted in altered catabolism of fibrillar Aβ 1–42 in vitro [ 28 ]. From this novel finding, we set out to understand the role of miR-155 in microglia, and how anti-inflammatory skewing of these cells impacted Aβ plaque pathology in AD mice.…”