DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease

Eur J Pharmacol. 2018 May 15;827:215-226. doi: 10.1016/j.ejphar.2018.03.024. Epub 2018 Mar 15.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3β in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

Keywords: APP/PS1 AD mice; Amyloid-β protein; GLP-1/GIP dual agonist; L-LTP; Long term memory; PI3K/AKT/GSK3β; Phosphorylated tau protein; Working memory.

MeSH terms

  • Alzheimer Disease / complications*
  • Animals
  • Cognition / drug effects
  • Cognitive Dysfunction / complications
  • Cognitive Dysfunction / drug therapy*
  • Disease Models, Animal
  • Female
  • Gastric Inhibitory Polypeptide / agonists*
  • Glucagon-Like Peptide 1 / agonists*
  • Male
  • Maze Learning / drug effects
  • Memory, Short-Term / drug effects
  • Mice
  • Mice, Transgenic
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Phosphorylation / drug effects
  • Signal Transduction / drug effects
  • tau Proteins / metabolism

Substances

  • DA5-CH peptide
  • Peptides
  • tau Proteins
  • Gastric Inhibitory Polypeptide
  • Glucagon-Like Peptide 1