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

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

  • Neuropharmacology. 2018 Mar 15;131:190-199. doi: 10.1016/j.neuropharm.2017.11.048.
Ying Wang 1,  Song Chen 2,  Zheng Xu 3,  Suting Chen 4,  Wenbing Yao 5,  Xiangdong Gao 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: wangying1177@126.com.
  • 2 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: chensong07@hotmail.com.
  • 3 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: xzchjs@126.com.
  • 4 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: cstlittle@163.com.
  • 5 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: wbyao@cpu.edu.cn.
  • 6 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China. Electronic address: xdgao@cpu.edu.cn.
PMID: 29223528 DOI: 10.1016/j.neuropharm.2017.11.048
Abstract

Alterations of glycoprotein glycans contribute to a wide variety of diseases. Bisecting N-acetylglucosamine (GlcNAc) 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 GlcNAc 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 GlcNAc were increased in APP/PS1 mice and Aβ25-35-treated PC12 cells, and GLP-1 Receptor agonists (GLP-1RA) could downregulate aberrant neuronal expression of GnT-III and bisecting GlcNAc. We also found that GLP-1RA recovered the phosphorylation levels of Akt (Ser473) and GSK-3β (Ser9) and the levels of β-catenin in mice and cell models. Furthermore, the results indicated that inhibitor LY294002 attenuated these effects of GLP-1RA in PC12 cells, and β-catenin siRNA abolished the effect of GLP-1RA 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-3β/β-catenin signaling pathway in neurons.

Keywords

AD; Aβ; Bisecting N-glycans; GLP-1; GnT-III.

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