A novel GLP-1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Hippocampus. 2018 May;28(5):358-372. doi: 10.1002/hipo.22837. Epub 2018 Mar 5.

Abstract

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimer's disease (AD). Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP-1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7-month-old triple transgenic mouse model of AD (3xTg-AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP-1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long-term spatial memory of 3xTg-AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long-term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid-β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3β in the hippocampus of the 3xTg-AD mice. These results demonstrate for the first time that the novel GLP-1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg-AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

Keywords: 3xTg-AD mice; GLP-1/GIP/Gcg triagonist; amyloid-β (Aβ) protein; learning and memory; long-term potentiation; p-CAMKII; p-CREB; p-GSK3β; phosphorylated tau protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Animals
  • Blood Glucose / drug effects
  • Body Weight / drug effects
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology
  • Cognition Disorders / pathology
  • Disease Models, Animal
  • Female
  • Gene Expression / drug effects
  • Glucagon-Like Peptide 1 / agonists*
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Long-Term Potentiation / drug effects
  • Male
  • Memory / drug effects
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuroprotective Agents / pharmacology*
  • Nootropic Agents / pharmacology
  • Receptors, Gastrointestinal Hormone / agonists*
  • Receptors, Glucagon / agonists*

Substances

  • Blood Glucose
  • Neuroprotective Agents
  • Nootropic Agents
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1
  • gastric inhibitory polypeptide receptor