Two dual GLP‐1/GIP receptor agonists show superior protective properties compared to liraglutide in the APP/PS1 mouse model of Alzheimer’s disease

Abstract Background Type II diabetes is a risk factor for developing AD, and we have previously tested liraglutide, an analogue of glucagon‐like peptide 1 (GLP‐1) that is on the market to treat diabetes, in patients with MCI/Alzheimer’s disease (ELAD study) and shown that it improves cognition and memory (ADASexec) and reduces shrinking of the temporal lobe and grey cortical matter (MRI scans). Novel dual GLP‐1/GIP receptor agonists have been developed by us that can enter the brain at a higher rate than drugs that had been developed to treat diabetes. Here, we tested the protective effects of the dual agonists DA4‐JC and DA5‐CH, and DA4‐JC in direct comparison with liraglutide in the APP/PS1 mouse model of AD. Methods First we tested the dual GLP‐1/GIP agonist DA4‐JC and compared it with liraglutide at equal doses of 10nmol/kg bw ip. once‐daily for 8 weeks in the APP/PS1 transgenic mouse model of AD. DA5‐CH was tested separately in the same model. Memory formation in the water maze, synaptic plasticity (LTP) in area CA1 of the hippocampus using in vivo electrophysiology techniques, amyloid plaque load, and chronic inflammation was evaluated using histological and western blot techniques. Results When comparing DA4‐JC with the GLP‐1 analogue liraglutide in the APP/PS1 mouse model of AD, DA4‐JC was more effective in reversing memory loss in the water maze task, was superior in enhancing synaptic plasticity (LTP) in the hippocampus, in reducing amyloid plaque load in the cortex, and in lowering pro‐inflammatory cytokine levels of TNF‐alpha and IL‐1ß in the brain compared to liraglutide. DA5‐CH also reduced memory impairments, amyloid plaque load in the brain, and normalized synaptic plasticity in the hippocampus while reducing inflammation in the brain. Conclusion The results show that the dual GLP‐1/GIP receptor agonists DA4‐JC and DA5‐CH are effective in treating AD and show great promise to be a superior treatment for AD than liraglutide.