On November 20, a research team led by Professor Sun Jin-Peng from the School of Basic Medical Sciences Shandong University and Peking University, in collaboration with Professor He Ju-Fang from City University of Hong Kong, Professor Zhang Yong and Associate Professor Tie Lu from Peking University, Professor Du Yang from The Chinese University of Hong Kong, Shenzhen, and Professor Tang Yi from Beijing Xuanwu Hospital, published a research paper online in Cell titled "Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment."

The study addressed a clinically-driven question by integrating analyses of clinical samples with animal models to elucidate the functional roles of distinct CCKBR downstream G protein signaling pathways in Alzheimer's disease (AD) progression. Through mechanistic investigation of how the endogenous agonist CCK8s activates different G proteins (Gs, Gq, Gi), the research revealed the molecular basis of CCKBR signaling bias. This fundamental understanding enabled the rational design of 3r1, a therapeutically promising Gq-biased agonist. Using animal models and transcriptomic analyses, the team demonstrated that 3r1 operates through the CCKBR-Gq-Plcb4-Adam10 signaling axis to suppress neuronal/synaptic damage and clear Aβ deposition. These findings establish a novel strategic approach for precision medicine in Alzheimer's disease treatment.

Wang Jia-Le and Sha Xue-Ying from the School of Basic Medical Sciences, Peking University Health Science Center; Shao Yue from City University of Hong Kong; Zhang Zi-Hao from the School of Basic Medical Sciences Shandong University; Professor Huang Shen-Ming from Jinan University; Researcher Lin Hui from the School of Basic Medical Sciences, Peking University Health Science Center; and Gan Shi-Yi from The Chinese University of Hong Kong, Shenzhen, are co-first authors. Professor Sun Jin-Peng, Professor He Ju-Fang, Professor Zhang Yong, Associate Professor Tie Lu, Professor Du Yang, and Professor Tang Yi served as co-corresponding authors. Critical contributions to this work were provided by Professor Xiao Peng and Professor Yang Fan from the School of Basic Medical Sciences Shandong University, as well as Professor Cheng Jie and Professor Wang Lu-Wen from the Advanced Medical Research Institute, Shandong University.

The research team detected cerebrospinal fluid samples from Alzheimer's disease patients and observed a progressive decline in CCKBR-mediated Gq signaling activity alongside increasing Gi signaling activity as the disease advanced. Their findings further indicated that activation of either Gs or Gq signaling pathways downstream of CCKBR exerts neuroprotective effects, whereas the Gi pathway is not involved in this process. Clinical sample analysis revealed a significant correlation between AD severity and reduced CCK8s levels coupled with elevated CCK4 levels in cerebrospinal fluid, suggesting that CCKBR signaling imbalance may play an important role in AD pathogenesis. Collectively, these results demonstrate the positive regulatory function of the CCKBR-Gq signaling axis in AD progression, highlighting its therapeutic targeting as a promising strategy for Alzheimer's disease treatment.

The research team successfully resolved the cryo-EM structures of CCK8s in complex with CCKBR and three distinct G proteins (Gs/Gq/Gi). Based on these structural insights, they developed the Gi-biased agonists Lyz-866 and z-44, as well as the Gq-biased agonist 3r1. Only 3r1 treatment significantly improved spatial learning and memory in mice, while also reducing Aβ plaque deposition and Tau protein phosphorylation. Further transcriptomic analysis revealed the molecular mechanism underlying 3r1-mediated neuroprotection, which operates through the novel CCKBR-Gq-PLCB4-ADAM10 signaling axis. In summary, this study is the first to elucidate the therapeutic potential of CCKBR biased signaling for Alzheimer's disease. The developed Gq-biased agonist 3r1 exhibits favorable pharmacokinetic properties, offering a new direction for precision medicine in AD treatment.

Professor Sun Jin-Peng's team has long been dedicated to research in microenvironment pharmacology and sensory pharmacology. Their systematic investigations have elucidated mechanisms through which membrane receptors perceive microenvironmental cues and regulate physiological functions. The team's landmark discoveries include the identification of GPCRs for auditory and balance perception, characterization of a membrane receptor subfamily for steroid hormones, and revelation of ceramide's membrane receptor. They have also developed therapeutic candidates targeting type 1 diabetes, atopic dermatitis, and muscle mass enhancement. As corresponding authors, Professor Sun and his team have published over 110 papers in prestigious journals including Nature (9 papers), Science (2 papers, with 1 featured as cover), Cell (6 papers, with 1 featured as cover), Cell Metabolism (2 papers), Nature Metabolism (2 papers), Nature Chemical Biology (4 papers), and Cell Research (4 papers). Their work establishes them at the international forefront of membrane receptor research in microenvironment sensing and ligand recognition. This research received support from the New Cornerstone Science Foundation, National Key R&D Program of China, National Science Fund for Distinguished Young Scholars, NSFC Key Program, NSFC Major Research Program, Shandong Provincial Key R&D Program, and Changping Laboratory Scientific Fund.