The Pro-Inflammatory Microrna Mir-155 Influences Fibrillar Beta-Amyloid(1-42) Catabolism By Microglia
GLIA(2021)
摘要
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.
更多查看译文
关键词
catabolism, fibrillar A ss 1-42, miR-146a, miR-155, miRNAs, primary microglia
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要