The article details a structural and pharmacological approach to treating Alzheimer’s disease (AD) by targeting the cholecystokinin B receptor (CCKBR), a G protein-coupled receptor crucial for memory and learning. The authors used cryo-electron microscopy to visualize the CCKBR complex bound to various G protein subtypes (Gq, Gs, and Gi), establishing that distinct receptor conformations are responsible for specific signal bias. This structural information enabled the rational design of synthetic small-molecule ligands, resulting in compounds like the exclusively Gi-biased agonist z-44 and the potent Gq-biased agonist 3r1. Crucially, only the brain-penetrant compound 3r1 demonstrated therapeutic potential in mouse models, significantly improving cognitive function and reducing AD pathology, whereas the Gi-biased agonist had no effect. The beneficial mechanism of 3r1 was identified as the biased activation of the CCKBR-Gq signaling cascade, which promotes neuronal health and reduces plaque formation by upregulating the ADAM10 and PLCB4 proteins.

References:

• Wang J L, Sha X Y, Shao Y, et al. Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment[J]. Cell, 2025.