Microglial activation depends on beta-amyloid conformation: role of the formylpeptide receptor 2.
Alzheimer's disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Abeta) complexes or senile plaques. Abeta peptide is firstly produced as monomers, readily aggregating to form multimeric complexes, of which the smallest aggregates are known to be the most neurotoxic. In AD patients, abundant reactive microglia migrate to and surround the Abeta plaques. Though it is well known that microglia are activated by Abeta, little is known about the peptide conformation and the signaling cascades responsible for this activation. In this study, we have stimulated murine microglia with different Abeta(1-42) forms, inducing an inflammatory state, which was peptide conformation-dependent. The lightest oligomeric forms induced a more violent inflammatory response, whereas the heaviest oligomers and the fibrillar conformation were less potent inducers. BocMLF, a formylpeptide chemotactic receptor 2 antagonist, decreased the oligomeric Abeta-induced inflammatory response. The Abeta-induced signal transduction was found to depend on phosphorylation mechanisms mediated by MAPKs and on activator protein 1/nuclear factor kappa-light-chain-enhancer of activated B cells pathways activation. These results suggest that the reactive microgliosis intensity during AD might depend on the disease progression and consequently on the Abeta conformation production. The recognition of Abeta by the formylpeptide chemotactic receptor 2 seems to be a starting point of the signaling cascade inducing an inflammatory state.
Heurtaux
Tony
T
Faculty of Science, Technology and Communication, University of Luxembourg, Luxembourg, Luxembourg. tony.heurtaux@uni.lu
Michelucci
Alessandro
A
Losciuto
Sophie
S
Gallotti
Christian
C
Felten
Paul
P
Dorban
Gauthier
G
Grandbarbe
Luc
L
Morga
Eleonora
E
Heuschling
Paul
P
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000502:physiology; D000818:Animals; D001704:Biopolymers; D002460:Cell Line; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000502:physiology; D010766:Phosphorylation; D011487:Protein Conformation; D044042:Receptors, Formyl Peptide / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D016328:NF-kappa B; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D018808:Transcription Factor AP-1; C075222:amyloid beta-protein (1-42); C481578:formyl peptide receptor 2, mouse; D020928:Mitogen-Activated Protein Kinases