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ß Amyloid peptide (Aß₄₂) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages ¹

HIROSHI YAZAWA^*, ZU-XI YU, TAKEDA, YINGYING LE^*, WANGHUA GONG, VICTOR J. FERRANS, JOOST J. OPPENHEIM^*, CHOU CHI H. LI and JI MING WANG^*2

^* Laboratory of Molecular Immunoregulation and
Intramural Research Support Program, SAIC Frederick, Center for Cancer Research, National Cancer Institute at Frederick, Maryland 21702, USA; and
Pathology Section, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

²Correspondence: LMI, CCR, NCI-Frederick, Building 560, Room 31–40, Frederick, MD 21702, USA. E-mail: wangji{at}mail.ncifcrf.gov

The 42 amino acid form of ß amyloid (Aß₄₂) 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 Aß₄₂ 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 Aß₄₂ by using fluorescence confocal microscopy. We found that upon incubation with macrophages or HEK293 cells genetically engineered to express FPRL1, Aß₄₂ associated with FPRL1 and the Aß₄₂/FPRL1 complexes were rapidly internalized into the cytoplasmic compartment. The maximal internalization of Aß₄₂/FPRL1 complexes occurred by 30 min after incubation. Removal of free Aß₄₂ from culture supernatants at 30 min resulted in a progressive recycling of FPRL1 to the cell surface and degradation of the internalized Aß₄₂. However, persistent exposure of the cells to Aß₄₂ over 24 h resulted in retention of Aß₄₂/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 Aß₄₂, FPRL1 is also involved in the internalization of Aß₄₂, which culminates in the formation of fibrils only in macrophages.—Yazawa, H., Yu, Z.-X., Takeda, K., Le, Y., Gong, W., Ferrans, V. J., Oppenheim, J. J., Li, C. C. H., Wang, J. M. ß Amyloid peptide (Aß₄₂) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages.

Key Words: amyloid ß • Alzheimer’s disease • internalization • colocalization

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