Reversal of β-amyloid induced microglial toxicity in vitro by activation of Fpr2/3

Abstract

Background and PurposeMicroglial inflammatory activity is thought to be a major contributor to the pathology of neurodegenerative conditions such as Alzheimers disease (AD), and strategies to restrain their behaviour are under active investigation. Classically, anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution, the endogenous process whereby an inflammatory reaction is terminated, has not been fully investigated as a therapeutic approach in AD. In this study, we sought to provide proof-of-principal that the major pro-resolving actor, formyl peptide receptor 2, Fpr2, could be targeted to reverse microglial activation induced by the AD-associated pro-inflammatory stimulus, oligomeric {beta}-amyloid (oA{beta}). Experimental ApproachThe immortalised murine microglial cell line BV2 was employed as a model system to investigate the pro-resolving effects of the Fpr2 ligand QC1 upon oA{beta}-induced inflammatory, oxidative and metabolic behaviour. Cytotoxic behaviour of BV2 cells was assessed through use of co-cultures with retinoic acid-differentiated human SH-SY5Y cells. Key ResultsStimulation of BV2 cells with oA{beta} at 100nM did not induce classical inflammatory marker production but did stimulate production of reactive oxygen species (ROS), an effect that could be reversed by subsequent treatment with the Fpr2 ligand QC1. Further investigation revealed that oA{beta}-induced ROS production was associated with NADPH oxidase activation and a shift in BV2 cell metabolic phenotype, activating the pentose phosphate pathway and NADPH production, changes that were again reversed by QC1 treatment. Microglial oA{beta}-stimulated ROS production was sufficient to induce apoptosis of bystander SH-SY5Y cells, an effect that could be prevented by QC1 treatment. Conclusion and ImplicationsIn this study, we provide proof-of-concept data that indicate exploitation of the pro-resolving receptor Fpr2 can reverse damaging oA{beta}-induced microglial activation. Future strategies aiming to restrain neuroinflammation in conditions such as AD should examine pro-resolving actors as a mechanism to harness the brains endogenous healing pathways and limit neuroinflammatory damage.