The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1-42)-Induced Neuroinflammation in Mouse Models of Alzheimer's Disease

The major histopathological hallmarks of Alzheimer's disease (AD) include beta-amyloid (A beta) plaques, neurofibrillary tangles, and neuronal loss. A beta 1-42 (A beta(1-42)) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of A beta(1-42) were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2(-/-)) were treated with fibrillary A beta(1-42), and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and A beta load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the A beta(1-42)-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFkB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load. These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.

Automated summary

The study revealed that the new FPR2 agonist MR-39 had a suppressive effect on the inflammatory response and an improvement on the anti-inflammatory response in AD models, possibly through inhibiting the MyD88/TRAF6/NFkB signaling pathway and reducing NLRP3 inflammasome activation.