A novel Dual GLP-1/CCK Receptor Agonist Improves Cognitive Performance and Synaptogenesis in the 5 × FAD Alzheimer Mouse Model

May 8, 2025Molecular neurobiology

A new drug that activates two hormone receptors may improve thinking and brain cell connections in an Alzheimer's mouse model

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Abstract

The dual GLP-1/CCK receptor agonist improved memory and reduced inflammation in animal models of Alzheimer's disease.

Memory performance improved in water maze and Y-maze tests.
Chronic inflammation markers, including NLRP3, IL-10, and TNFα, returned to physiological levels.
Amyloid aggregates in the brain were reduced by the treatment.
The dual agonist enhanced growth factor signaling, increasing levels of BDNF and TrkB.
In synaptic evaluations, synapse numbers normalized and the synaptic cleft was wider in treated 5xFAD mice.
The dual GLP-1/CCK agonist was superior to Liraglutide in memory tests and BDNF upregulation.

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Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor. Cholecystokinin (CCK) is another peptide hormone, growth factor and neurotransmitter. Both peptide hormones have shown good neuroprotective effects in animal models of Alzheimer's disease (AD). In this study, we tested the effects of a dual GLP-1/CCK (25 nmol/kg ip. for 14 days) receptor agonist that had previously shown good effects in animal models of diabetes. The GLP-1 analogue Liraglutide (50 nmol/kg ip.) was used as a positive control. Memory was improved in the water maze and the Y-maze, spontaneous activity was increased, the chronic inflammation response had been reduced and levels of NLRP3, IL-10 and TNFα were brought back to physiological levels. Levels of amyloid aggregates in the brain were reduced by the drugs. The expression of proteins SIRPα and CD47 which is related to reduced inflammation levels was reduced. Importantly, growth factor signalling was much improved and growth levels of BDNF, TrkB receptor, p-CREB, and an upregulation of the PI3K-AKT signalling pathway had been observed. Post-synaptic density protein (PSD) and synaptophysin levels were reduced, too. In transmission electron microscope analysis, the synaptic cleft was found to be wider in 5xFAD mice. In Golgi stain evaluations, synapse numbers were brought back to normal levels by the drugs. In a direct comparison with Liraglutide, the dual GLP-1/CCK receptor agonist was superior in the water maze tests and in the upregulation of BDNF and TrkB levels in the brain. In other parameters, the dual agonist and Liraglutide showed comparable effects. In conclusion, the combination of GLP-1 and CCK receptor activation did not show overall improvements over single GLP-1 receptor activation.

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A novel Dual GLP-1/CCK Receptor Agonist Improves Cognitive Performance and Synaptogenesis in the 5 × FAD Alzheimer Mouse Model

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