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.

The Expression of Formyl Peptide Receptor 1 is Correlated with Tumor Invasion of Human Colorectal Cancer

“…Chemotaxis assays were performed using a 48-well chemotaxis chamber (Neuro Probe, Gaithersburg, MD) according to the published procedures 32 . For SW480 and HT29 cells, after 12 h incubation with fMLF (1 μM), with or without a 15 min pretreatment with cyclosporine H (1 μM) or Boc1 (10 μM) at 37 °C, the filter was removed and fixed with methanol and stained with 0.1% crystal violet.…”

Amyloid beta: structure, biology and structure-based therapeutic development

“…The scavenger receptors (SRs) include scavenger receptor A-1 (SCARA-1), MARCO, scavenger receptor B-1 (SCARB-1), CD36 and the receptor for advanced glycation end product (RAGE) [129] . The G-protein coupled receptor (GPCR) group includes formyl peptide receptor 2 (FPR2) and chemokine-like receptor 1 (CMKLR1) [130] , and the toll-like receptor (TLR) group includes TLR2, TLR4, and the co-receptor CD14 [131] . Functionally, SCARA-1 and CMKLR1 participate the uptake of Aβ, and RAGE is responsible for the activation of microglia and production of proinflammatory mediators in response to Aβ binding.…”

Targeting neuroinflammation in Alzheimer’s disease

“…This is possible because of the presence of proinflammatory receptors on their surface. Microglia is able to identify and bind Aβ oligomers and fibrils and the amyloid precursor protein (APP)57 through a large number of receptors, including scavenger receptor class A type 1, MARCO, scavenger receptor class B member 1, CD36, and the receptor for advanced glycation end product,58,59 G protein-coupled receptors formyl peptide receptor 2 60 and chemokine-like receptor 1,61 toll-like receptors (TLRs) TLR2,62 TLR4, and the CD14 coreceptor, and α6β1 integrin 63. The outcome of the bond between Aβ and these receptors is the production of inflammatory mediators such as cytokines (interleukin [IL]-1α, IL-1β, IL-6, IL-8, IL-12, IL-18, and IL-23, interferon (IFN)-γ, tumor necrosis factor [TNF]-α, and granulocyte-macrophage colony-stimulating factor [GM-CSF]),64,65 chemokines (monocyte chemotactic protein 1 (MCP1), MCP-113, fractalkine),66,67 chemoattractant proteins, prostaglandins, complement factors, thromboxanes, pentraxins, NO, reactive oxygen species, leukotrienes, proteases, protease inhibitors, adhesion molecules (interaction between CD40-CD40 ligand CD40L),68 coagulation factors, and C-reactive protein, most of which are detectable in AD animal and/or in the brain or cerebrospinal fluid of AD patients 25,69,70.…”