Program

PO1-1-59

Pharmacological characterization of the amyloid beta peptide Abeta42 for its modulation of the chemerin receptor CMKLR1

[Speaker] Richard D Ye:1
[Co-author] Shuo Zhang:2, Dan Liao:2, Hao Gong:2
1:University of Macau, Macao, 2:Shanghai Jiao Tong University, China

BACKGROUND Accumulation of amyloid beta peptides (Abeta) in the brain is a prominent pathological feature of Alzheimer's disease, but the signaling property of Abeta has not been thoroughly investigated. Given that Abeta is an agonist of the chemerin receptor, chemokine-like receptor 1 (CMKLR1), we investigated potential modulation of the receptor by Abeta.
METHODS Cells expressing CMKLR1 were incubated with Abeta42 before stimulation with the C9 peptide agonist of chemerin. Calcium mobilization, cAMP inhibition and MAP kinase phosphorylation were measured. A C-terminal tagged receptor was prepared for measurement of ligand-induced FRET.
RESULTS Binding of both Abeta42 and the C9 peptide induced CMKLR1 internalization, but only the Abeta42-induced receptor internalization through clathrin-coated pits. Abeta42 but not C9 stimulated beta-arrestin2 translocation to plasma membranes. A robust Ca2+ flux was observed following C9 stimulation, whereas Abeta42 was ineffective even at micromolar concentrations. Despite its low potency for calcium mobilization, Abeta42 preincubation altered C9-induced Ca2+ flux at high picomolar to low nanomolar range. A biphasic dose curve was observed, indicating that Abeta42 concentration is critical to the modulatory effects it produced. Likewise, preincubation with Abeta42 altered C9-induced ERK phosphorylation but the dose curve was different from that of Ca2+ flux and cAMP inhibition. These findings indicate a reciprocal regulatory mechanism not seen with other ligands, suggesting that Abeta42 may be interacting with the receptor at a different site. FRET assay confirmed Abeta42 modulation at the receptor level and not through its downstream signaling pathways.
CONCLUSION The above results identify a novel feature of the amyloid beta peptide Abeta42 for its modulation of a G protein-coupled receptor. Further exploration of the Abeta42-receptor interaction may help to understand how production and accumulation of Abeta42 alter normal brain function in Alzheimer's disease.
KEYWORDS Amyloid beta peptide; neuroinflammation; G protein-coupled receptor
GRANT SUPPORT Supported by grants MYRG2016-00152-ICMS-QRCM from University of Macau and FDCT072/2015/A2 from Science and Technology Development Fund of Macau.
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