The Chemerin Receptor CMKLR1 is a Functional Receptor for Amyloid-β Peptide

Amyloid-beta peptides such as A beta(1-42) (A beta(42)) play a pivotal role in the progression of Alzheimer's disease (AD). A beta(42) is neurotoxic and can activate microglial cells. These cells in turn migrate toward senile (neuritic) plaques and help to clear A beta deposits through an endocytotic mechanism. It is of potential significance to characterize the A beta(42) receptors that mediate microglia chemotaxis and A beta(42) 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 A beta(42) colocalized in hippocampus and cortex of A beta PP/PS1 transgenic mice. Moreover, A beta(42) bound specifically to CMKLR1 in stably transfected rat basophilic leukemia (RBL) cells (CMKLR1-RBL), suggesting that CMKLR1 is a receptor for A beta(42). A beta(42) 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 A beta(42) induced CMKLR1-dependent cell migration through activation of the ERK1/2, PKA, and Akt pathways, but not Ca2+ mobilization. A beta(42) stimulation of CMKLR1-RBL cells and primary glial cells led to internalization of the A beta(42)-CMKLR1 complex, suggesting a potential role for CMKLR1in A beta(42) clearance. Taken together, these results indicate that A beta(42) activates CMKLR1, leading to glia cell migration and clearance of A beta(42). CMKLR1 is a new addition to the repertoire of cell surface molecules that are responsible for A beta processing and clearance.