Amyloid Beta Peptide Modulates the Signaling Property of Chemokine‐like Receptor 1

Abstract

OBJECTIVEAmyloid beta peptides (Aβ) are the main constituents of the amyloid plaques found in the brains of Alzheimer patients. While Aβ is proinflammatory and contributes to the development of Alzheimer's disease, its signaling property remains unclear. The present study investigates how Aβ modulates signaling of one of its receptors, the chemokine‐like receptor 1 (CMKLR1, ChemR23).METHODSCells expressing CMKLR1 were incubated with Aβ42 before stimulation with another agonist of the CMKLR1, the C9 peptide. Calcium mobilization, cAMP inhibition and MAP kinase activation were measured. Intramolecular FRET was determined using CMKLR1 constructs containing an ECFP attached to the C‐terminus.RESULTSBinding of both Aβ42 and the C9 peptide induced CMKLR1 internalization, but only the Aβ42‐induced receptor internalization involved clathrin‐coated pits. Likewise, Aβ42 but not C9 stimulated β‐arrestin2 translocation to plasma membranes. A robust Ca2+ flux was observed following C9 stimulation, whereas Aβ42 was ineffective even at micromolar concentrations. Despite its low potency in calcium mobilization assay, Aβ42 was able to alter C9‐induced Ca2+ flux with potentiation at concentrations as low as 0.1 – 1 nM. However, at higher concentrations the effect was diminished. Similar effects were seen with the C9‐induced ERK phosphorylation but the dose curve was different from that of Ca2+ flux and cAMP inhibition, suggesting a reciprocal regulatory mechanism. Intramolecular FRET assay confirmed that Aβ42 modulates CMKLR1 rather than its downstream signaling pathways.CONCLUSIONThese findings suggest that long‐term exposure to Aβ42 may alter the signaling properties of its receptors, thereby influence the pathology of Alzheimer's disease. The reciprocal regulation of CMKLR1 by Aβ provides a novel mechanism by which a ligand dose‐dependently modulates the response of its receptor to another ligand.Support or Funding InformationSupported by grants SRG2015‐00047‐ICMS‐QRCM and MYRG2016‐00152‐ICMS‐QRCM from University of Macau and by grant 31470865 from NSFC.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.