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

Mol Neurobiol. 2021 Dec;58(12):6203-6221. doi: 10.1007/s12035-021-02543-2. Epub 2021 Sep 1.


The major histopathological hallmarks of Alzheimer's disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1-42 (Aβ1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ1-42 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 Aβ1-42, 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 Aβ load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aβ1-42-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/NFкB 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.

Keywords: APP/PS1 double-transgenic mouse model; Alzheimer’s disease; Compound MR-39; Formyl peptide receptor 2; NLRP3 inflammasome pathway; Organotypic hippocampal cultures.

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use*
  • Disease Models, Animal
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Neuroinflammatory Diseases / drug therapy*
  • Neuroinflammatory Diseases / metabolism
  • Neuroinflammatory Diseases / pathology
  • Peptide Fragments / pharmacology*
  • Receptors, Formyl Peptide / agonists*


  • Amyloid beta-Peptides
  • Anti-Inflammatory Agents
  • Peptide Fragments
  • Receptors, Formyl Peptide
  • amyloid beta-protein (1-42)
  • formyl peptide receptor 2, mouse