GLP-1 receptor agonists downregulate aberrant GnT-III expression in Alzheimer's disease models through the Akt/GSK-3β/β-catenin signaling
| Autor: | Xiangdong Gao, Wenbing Yao, Song Chen, Su-Ting Chen, Zheng Xu, Ying Wang |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine endocrine system Cell Survival Down-Regulation Mice Transgenic N-Acetylglucosaminyltransferases PC12 Cells Neuroprotection Glucagon-Like Peptide-1 Receptor Amyloid beta-Protein Precursor Mice 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Alzheimer Disease Presenilin-1 Animals LY294002 Enzyme Inhibitors RNA Small Interfering Maze Learning Receptor Protein kinase B Glucagon-like peptide 1 receptor Pharmacology Memory Disorders Venoms Chemistry Rats Oncogene Protein v-akt Disease Models Animal 030104 developmental biology Cancer research Exenatide Phosphorylation Signal transduction Peptides 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Neuropharmacology. 131:190-199 |
| ISSN: | 0028-3908 |
| DOI: | 10.1016/j.neuropharm.2017.11.048 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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