Amyloid-beta induces chemotaxis and oxidant stress by acting at formylpeptide receptor 2, a G protein-coupled receptor expressed in phagocytes and brain

Amyloid-beta, the pathologic protein in Alzheimer's disease, induces chemot axis and production of reactive oxygen species in phagocytic cells, but mec hanisms have not been fully defined. Here me provide three lines of evidenc e that the phagocyte G protein-coupled receptor (N-formylpeptide receptor 2 (FPR2)) mediates these amyloid-beta -dependent functions in phagocytic cel ls. First, transfection of FPR2, but not related receptors, including the o ther known N-formylpeptide receptor FPR, reconstituted amyloid-beta -depend ent chemotaxis and calcium flux in HEK 293 cells. Second, amyloid-beta indu ced both calcium flux and chemotaxis in mouse neutrophils (which express en dogenous FPR2) with similar potency as in FPR2-transfected HEK 293 cells, T his activity could be specifically desensitized in both cell types by prein cubation with a specific FPR2 agonist, which desensitizes the receptor, or with pertussis toxin, which uncouples it from G(i)-dependent signaling. Thi rd, specific and reciprocal desensitization of superoxide production was ob served when N-formylpeptides and amyloid-beta were used to sequentially sti mulate neutrophils from FPR -/- mice, which express FPR2 normally. Potentia l biological relevance of these results to the neuroinflamma. tion associat ed with Alzheimer's disease was suggested by two additional findings: first , FPR2 mRNA could be detected by PCR in mouse brain; second, induction of F PR2 expression correlated with induction of calcium flux and chemotaxis by amyloid-beta in the mouse microglial cell line N9, Further, in sequential s timulation experiments with N9 cells, N-formylpeptides and amyloid-beta wer e able to reciprocally cross-desensitize each other. Amyloid-beta was also a specific agonist at the human counterpart of FPR2, the FPR-like 1 recepto r. These results suggest a unified signaling mechanism for linking amyloid- beta to phagocyte chemotaxis and oxidant stress in the brain.