The Dual GLP-1/GIP Receptor Agonist DA4-JC Shows Superior Protective Properties Compared to the GLP-1 Analogue Liraglutide in the APP/PS1 Mouse Model of Alzheimer's Disease

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  • Mark Maskery
  • Elizabeth Mary Goulding
  • Simon Gengler
  • Josefine Ulrikke Melchiorsen
  • Rosenkilde, Mette
  • Christian Holscher

Alzheimer's disease (AD) is a neurodegenerative disorder for which there is no cure. Here, we test a dual GLP-1/GIP receptor agonist (DA4-JC) that has a cell penetrating sequence added to enhance blood-brain barrier penetration. We show in a receptor activity study that DA4-JC has balanced activity on both GLP-1 and GIP receptors but not on GLP-2 or Glucagon receptors. A dose-response study in the APP/PS1 mouse model of AD showed both a dose-dependent drug effect on the inflammation response and the reduction of amyloid plaques in the brain. When comparing DA4-JC with the GLP-1 analogue liraglutide at equal doses of 10nmol/kg bw ip. once-daily for 8 weeks, DA4-JC was more effective in reversing memory loss, enhancing synaptic plasticity (LTP) in the hippocampus, reducing amyloid plaques and lowering pro-inflammatory cytokine levels in the brain. The results suggest that DA4-JC may be a novel treatment for AD.

Original languageEnglish
Article number1533317520953041
JournalAmerican Journal of Alzheimer's Disease and Other Dementias
Volume35
Number of pages11
ISSN1533-3175
DOIs
Publication statusPublished - 2020

    Research areas

  • insulin, growth factor, brain, inflammation, TNF-alpha, synaptic plasticity

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