β amyloid peptide (Aβ42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages

The 42 amino acid form of beta amyloid (A beta (42)) plays a pivotal role in neurotoxicity and the activation of mononuclear phagocytes in Alzheimer's disease (AD). Our recent study revealed that FPRL1, a G-protein-coupled receptor, mediates the chemotactic and activating effect of A beta (42) on mononuclear phagocytes (monocytes and microglia), suggesting that FPRL1 may be involved in the proinflammatory responses in AD. We investigated the role of FPRL1 in cellular uptake and the subsequent fibrillar formation of A beta (42) by using fluorescence confocal microscopy. We found that upon incubation with macrophages or HEK293 cells genetically engineered to express FPRL1, A beta (42) associated with FPRL1 and the A beta (42)/FPRL1 complexes were rapidly internalized into the cytoplasmic compartment. The maximal internalization of A beta (42)/FPRL1 complexes occurred by 30 min after incubation. Removal of free A beta (42) from culture supernatants at 30 min resulted in a progressive recycling of FPRL1 to the cell surface and degradation of the internalized A beta (42). However, persistent exposure of the cells to A beta (42) over 24 h resulted in retention of A beta (42)/FPRL1 complexes in the cytoplasmic compartment and the formation of Congo red positive fibrils in macrophages but not in HEK 293 cell transfected with FPRL1. These results suggest that besides mediating the proinflammatory activity of A beta (42), FPRL1 is also involved in the internalization of A beta (42), which culminates in the formation of fibrils only in macrophages.