GLP-1 receptor agonists downregulate aberrant GnT-III expression in Alzheimer's disease models through the Akt/GSK-3β/β-catenin signaling

Alterations of glycoprotein glycans contribute to a wide variety of diseases. Bisecting N-acetylglucosamine (GIcNAc) levels increased in the cerebrospinal fluid of most Alzheimer's disease (AD) patients, and the mRNA levels of N-acetylglucosaminyltransferase III (GnT-III), a glycosyltransferase responsible for synthesizing a bisecting GIcNAc residue, were found highly expressed in the brains of AD patients. In our previous studies, glucagon-like peptide-1 (GLP-1) and its mimetics showed neuroprotective effects. Here, we confirmed that four weeks' treatment of exendin-4 could rescue memory deficits and neuropathological changes in APP/PS1 mice. We further explored the underlying mechanism and especially the role of GnT-III in it. We demonstrated for the first time that the levels of GnT-III and bisecting GIcNAc were increased in APP/PS1 mice and A beta(25-35)-treated PC12 cells, and GLP-1 receptor agonists (GLP-1RA) could downregulate aberrant neuronal expression of GnT-III and bisecting GIcNAc. We also found that GLP-1RA recovered the phosphorylation levels of Akt (Ser473) and GSK-3 beta (Ser9) and the levels of beta-catenin in mice and cell models. Furthermore, the results indicated that inhibitor LY294002 attenuated these effects of GLP-IRA in PC12 cells, and beta-catenin siRNA abolished the effect of GLP-IRA on GnT-III. In summary, our results suggest that GnT-III plays an important role in AD and GLP-1RA could downregulate aberrant GnT-III expression through the Akt/GSK-3 beta/beta-catenin signaling pathway in neurons. (C) 2017 Elsevier Ltd. All rights reserved.