Potential role of the formyl peptide receptor-like 1 (FPRL1) in inflammatory aspects of Alzheimer's disease.
Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by the presence of multiple senile plaques in the brain tissue, which are also associated with considerable inflammatory infiltrates. Although the precise mechanisms of the pathogenesis of AD remain to be determined, the overproduction and precipitation of a 42 amino acid form of beta amyloid (Abeta(42)) in plaques have implicated Abeta in neurodegeneration and proinflammatory responses seen in the AD brain. Our recent studies revealed that the activation of formyl peptide receptor-like 1 (FPRL1), a seven-transmembrane, G-protein-coupled receptor, by Abeta(42) may be responsible for accumulation and activation of mononuclear phagocytes (monocytes and microglia). We further found that upon binding FPRL1, Abeta(42) was rapidly internalized into the cytoplasmic compartment in the form of Abeta(42)/FPRL1 complexes. Persistent exposure of FPRL1-expressing cells to Abeta(42) resulted in intracellular retention of Abeta(42)/FPRL1 complexes and the formation of Congo-red-positive fibrils in mononuclear phagocytes. Our observations suggest that FPRL1 may not only mediate the proinflammatory activity of Abeta(42) but also actively participate in Abeta(42) uptake and the resultant fibrillar formation. Therefore, FPRL1 may constitute an additional molecular target for the development of therapeutic agents for AD.
Cui
Youhong
Y
Biochemistry Section, Lanzhou Military Medical University, Lanzhou, People's Republic of China.
Le
Yingying
Y
Yazawa
Hiroshi
H
Gong
Wanghua
W
Wang
Ji Ming
JM
D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D006801:Humans; D017628:Microglia / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000276:immunology*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000276:immunology*
D016229:Amyloid beta-Peptides; C105101:FPR2 protein, human; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; C075222:amyloid beta-protein (1-42)