A novel dual CCK/ GLP-1 receptor agonist ameliorates cognitive impairment in 5 × FAD mice by modulating mitophagy via the PINK1/Parkin pathway

To date, no therapeutic drugs available on the market can effectively reverse the progression of Alzheimer's disease (AD). Although Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and Cholecystokinin (CCK) RAs have shown some promise in AD research, little is known about the neuroprotective effects of a novel dual CCK/GLP-1 RA in AD. This study sought to examine the effects of the novel dual CCK/GLP-1 RA on cognitive performance in an AD mouse model and to explore the associated mechanisms. Our findings indicate that dual CCK/GLP-1 RA improved cognitive deficits, reduced amyloid-beta (Aβ) accumulation, and alleviated mitochondrial damage in 5 × FAD mice by inducing mitophagy. In an in vitro model of AD cells induced by Aβ, CCK/GLP-1 RA could exert neuroprotective effects by regulating PINK1/Parkin-mediated mitophagy. These data reveal for the first time that the new CCK/GLP-1 RA modulates mitophagy via PINK1/Parkin pathway and enhances cognitive function in the 5 × FAD animal model. Moreover, the performance of the CCK/GLP-1 RA in certain indicators was superior to that of GLP-1 analogue liraglutide, suggesting that it may represent a more promising therapeutic option for AD.