Chemokine-like Receptor1is A Functional Receptor For β-amyloid

Amyloid β (Aβ) play a pivotal role in the progression ofAD throughits neurotoxic and activating effects on glial cells (microglia and astrocytes)which either clearingAβ deposits through an uptake mechanism andrelease inflammatory mediators. In a survey of public whole genomeexpression datasets and animal experiments, we found that the mRNAexpression of a G-protein-coupled receptor named chemokine-likereceptor1(CMKLR1), is up-regulated in AD brains and mouse brainsafter systemic LPS administration. Then, we further explore whether thereis an interaction between Aβ42and CMKLR1. We found thatAβ42inducedcell migration in mouse primary cultured microglia, mouse microglial cellline N9, and CMKLR1transfected RBL cells at a dose dependent manner,suggesting CMKLR1is a function receptor ofAβ42. While mechanisticstudies showed thatAβ42induced migration through CMKLR1by activating of MAPKs, PI3K and PKA pathway, but independent of Ca2+signaling. In addition, CMKLR1colocalized withAβ in the cortex andhippocampus of APP/PS11transgenic mouse brain.Aβ42inducedCMKLR1internalization in CMKLR1-RBL cells and both Aβ42andCMKLR1were internalized into the cytoplasm in glial cells. These resultssuggest that CMKLR1is a functional receptor ofAβ42, and CMKLR1maymediate inflammation in AD and is a potential target for developingtherapeutic agents.