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

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...

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Bibliographic Details
Published in:American journal of Alzheimer's disease and other dementias 2020-01, Vol.35, p.1533317520953041-1533317520953041
Main Authors: Maskery, Mark, Goulding, Elizabeth Mary, Gengler, Simon, Melchiorsen, Josefine Ulrikke, Rosenkilde, Mette Marie, Hölscher, Christian
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Amyloid beta-Protein Precursor
Animals
Disease Models, Animal
Glucagon-Like Peptide 1
Liraglutide - pharmacology
Mice
Mice, Transgenic
Original Research
Pharmaceutical Preparations
Presenilin-1
Receptors, Gastrointestinal Hormone
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Summary: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.
ISSN:1533-3175
1938-2731
DOI:10.1177/1533317520953041