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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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. / Maskery, Mark; Goulding, Elizabeth Mary; Gengler, Simon; Melchiorsen, Josefine Ulrikke; Rosenkilde, Mette Marie; Holscher, Christian.
In: American Journal of Alzheimer's Disease and Other Dementias, Vol. 35, 1533317520953041, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Maskery, Mark
AU - Goulding, Elizabeth Mary
AU - Gengler, Simon
AU - Melchiorsen, Josefine Ulrikke
AU - Rosenkilde, Mette Marie
AU - Holscher, Christian
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - insulin
KW - growth factor
KW - brain
KW - inflammation
KW - TNF-alpha
KW - synaptic plasticity
U2 - 10.1177/1533317520953041
DO - 10.1177/1533317520953041
M3 - Journal article
C2 - 32959677
VL - 35
JO - American Journal of Alzheimer's Disease and other Dementias
JF - American Journal of Alzheimer's Disease and other Dementias
SN - 1533-3175
M1 - 1533317520953041
ER -
ID: 257084133