title: The chemerin receptor CMKLR1 is a functional receptor for amyloid-β peptide.
abstract: Amyloid-β peptides such as Aβ1-42 (Aβ42) play a pivotal role in the progression of Alzheimer's disease (AD). Aβ42 is neurotoxic and can activate microglial cells. These cells in turn migrate toward senile (neuritic) plaques and help to clear Aβ deposits through an endocytotic mechanism. It is of potential significance to characterize the Aβ42 receptors that mediate microglia chemotaxis and Aβ42 uptake. We found that the transcript of the chemerin receptor CMKLR1 was upregulated in the brain of AD patients and in mouse brain tissue following systemic LPS administration. CMKLR1 and Aβ42 colocalized in hippocampus and cortex of AβPP/PS1 transgenic mice. Moreover, Aβ42 bound specifically to CMKLR1 in stably transfected rat basophilic leukemia (RBL) cells (CMKLR1-RBL), suggesting that CMKLR1 is a receptor for Aβ42. Aβ42 induced migration of primary microglia, the mouse microglial cell line N9, and CMKLR1-RBL cells, but not untransfected RBL-2H3 cells. Mechanistic studies showed that Aβ42 induced CMKLR1-dependent cell migration through activation of the ERK1/2, PKA, and Akt pathways, but not Ca2+ mobilization. Aβ42 stimulation of CMKLR1-RBL cells and primary glial cells led to internalization of the Aβ42-CMKLR1 complex, suggesting a potential role for CMKLR1 in Aβ42 clearance. Taken together, these results indicate that Aβ42 activates CMKLR1, leading to glia cell migration and clearance of Aβ42. CMKLR1 is a new addition to the repertoire of cell surface molecules that are responsible for Aβ processing and clearance.
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors: Lei
authors: L
authors: Peng
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors: Yang
authors: Y
authors: Yu
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors: Jin
authors: J
authors: Liu
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors: Shuqin
authors: S
authors: Li
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors: Huiqiong
authors: H
authors: He
authors: Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, USA.
authors: Ni
authors: N
authors: Cheng
authors: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P.R. China Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, USA.
authors: Richard D
authors: RD
authors: Ye
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; C102741:CMKLR1 protein, human; C486456:CMKLR1 protein, mouse; C105101:FPR2 protein, human; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D043562:Receptors, G-Protein-Coupled; D044067:Receptors, Lipoxin; C075222:amyloid beta-protein (1-42); D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium
keywords: Alzheimer's disease; amyloid-β; chemerin receptor; chemotaxis; microglial cells