Signatures of resolution reprogramming in amyloid‐challenged microglia

Abstract

AbstractBackgroundSpecialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on innate immune cells like monocytes and microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the signatures ofMethodThe Ts65Dn mouse develops amyloid hyperexpression, neuroinflammation and neurodegeneration. We administered the SPM, Resolvin E1 (RvE1), for 1 month to control and Ts65Dn mice and measured memory using a series of tasks. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We then challenged Human innate immune cell culture models (monocytes and microglia) with amyloid‐beta and tau oligomer activation and/or administered RvE1 to promote resolution. We will employ RNASeq to learn how RvE1 resolution reprogramming affects transcriptional outcomes in these cell culture models.ResultRvE1 significantly reduced microglial activation and cytokine expression in the Ts65Dn mice, suggesting broad effects on central and peripheral innate immunity. We discovered that chronic RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family and in the PPAR‐gamma receptor and to specific signaling events. We are quantifying transcriptional outcomes to better define the nuclear program that underlies resolution.ConclusionWe have demonstrated that RvE1 modulates inflammation in a mouse model. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms.