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.
Keywords: TNF-alpha; brain; growth factor; inflammation; insulin; synaptic plasticity.