H. Yazawa et al., beta amyloid peptide (A beta(42)) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages, FASEB J, 15(13), 2001, pp. 2454-2462
The 42 amino acid form of beta amyloid (A beta (42)) plays a pivotal role i
n neurotoxicity and the activation of mononuclear phagocytes in Alzheimer's
disease (AD). Our recent study revealed that FPRL1, a G-protein-coupled re
ceptor, mediates the chemotactic and activating effect of A beta (42) on mo
nonuclear phagocytes (monocytes and microglia), suggesting that FPRL1 may b
e involved in the proinflammatory responses in AD. We investigated the role
of FPRL1 in cellular uptake and the subsequent fibrillar formation of A be
ta (42) by using fluorescence confocal microscopy. We found that upon incub
ation with macrophages or HEK293 cells genetically engineered to express FP
RL1, A beta (42) associated with FPRL1 and the A beta (42)/FPRL1 complexes
were rapidly internalized into the cytoplasmic compartment. The maximal int
ernalization of A beta (42)/FPRL1 complexes occurred by 30 min after incuba
tion. Removal of free A beta (42) from culture supernatants at 30 min resul
ted 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 comple
xes in the cytoplasmic compartment and the formation of Congo red positive
fibrils in macrophages but not in HEK 293 cell transfected with FPRL1. Thes
e results suggest that besides mediating the proinflammatory activity of A
beta (42), FPRL1 is also involved in the internalization of A beta (42), wh
ich culminates in the formation of fibrils only in macrophages.