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. Epub 2017 Dec 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Models, Animal
  • Down-Regulation / drug effects*
  • Enzyme Inhibitors / pharmacology
  • Exenatide
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology
  • Mice
  • Mice, Transgenic
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Oncogene Protein v-akt / genetics
  • Oncogene Protein v-akt / metabolism*
  • PC12 Cells
  • Peptides* / pharmacology
  • Peptides* / therapeutic use
  • Presenilin-1 / genetics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Venoms* / pharmacology
  • Venoms* / therapeutic use

Substances

  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Presenilin-1
  • RNA, Small Interfering
  • Venoms
  • Exenatide
  • N-Acetylglucosaminyltransferases
  • beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase
  • Oncogene Protein v-akt