2. Academic Validation
  3. Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment

Elucidating pathway-selective biased CCKBR agonism for Alzheimer's disease treatment

  • Cell. 2025 Nov 20:S0092-8674(25)01238-3. doi: 10.1016/j.cell.2025.10.034.
Jia-Le Wang 1,  Xue-Ying Sha 2,  Yue Shao 3,  Zi-Hao Zhang 4,  Shen-Ming Huang 5,  Hui Lin 6,  Shi-Yi Gan 7,  Nan Zhang 3,  Xin-Yi Xia 8,  Yu-Nan Sun 9,  Jin-Hui Ding 10,  Rui-Qi Zhao 11,  Jie Cheng 12,  Pan Shang 13,  Jin-Peng Wang 14,  Yan-Jun Liu 10,  Fan Yang 15,  Peng Xiao 16,  Lu-Wen Wang 17,  Dong-Yu Zhao 9,  Yi Tang 18,  Lu Tie 19,  Yang Du 20,  Yong Zhang 21,  Ju-Fang He 22,  Jin-Peng Sun 23
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing 100191, China; Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China; New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing 100191, China; Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 3 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China.
  • 4 New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, China.
  • 6 Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 7 Kobilka Institute of Innovative Drug Discovery, the Second Affiliated Hospital, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China.
  • 8 Department of Neurology, Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China.
  • 9 Department of Biomedical Informatics, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 10 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing 100191, China.
  • 11 Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China.
  • 12 New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 13 New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 14 Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission of People's Republic of China, IDG/McGovern Institute for Brain Research at Peking University, Beijing 100083, China.
  • 15 New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
  • 16 New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 17 NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China.
  • 18 Department of Neurology, Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, China. Electronic address: [email protected].
  • 19 Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 20 Kobilka Institute of Innovative Drug Discovery, the Second Affiliated Hospital, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong 518172, China. Electronic address: [email protected].
  • 21 Neuroscience Research Institute, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education, National Health Commission of People's Republic of China, IDG/McGovern Institute for Brain Research at Peking University, Beijing 100083, China. Electronic address: [email protected].
  • 22 Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China. Electronic address: [email protected].
  • 23 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodelling, Peking University, Beijing 100191, China; Department of Biophysics, School of Basic Medical Sciences, Peking University, Beijing, China; New Cornerstone Science Laboratory, Advanced Medical Research Institute, Shandong University, Jinan, Shandong 250012, China; NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China. Electronic address: [email protected].
PMID: 41270732 DOI: 10.1016/j.cell.2025.10.034
Abstract

Expressed in the entorhinal cortex (EC), the cholecystokinin (CCK) B receptor (CCKBR) plays an important role in memory and learning. Here, we identify that CCKBR-Gs and -Gq signaling, rather than CCKBR-Gi signaling, are beneficial for Alzheimer's disease (AD) treatment. Clinically, patients with more severe AD associated with lower CCKBR-Gq activity. The cryo-electron microscopy (cryo-EM) structures of CCKBR in complex with the endogenous agonist sulfated CCK8 (CCK8s) and 3 different G protein subtypes revealed that distinct receptor conformations contribute to selective G protein bias. Leveraging these structural insights, we rationally develop synthetic CCKBR agonists, including a Gi-biased agonist (z-44) and a Gq-biased agonist (3r1). Notably, 3r1 demonstrates therapeutic potential by ameliorating cognitive decline in 5×FAD mice, reducing the number of Amyloid-β plaques, and promoting long-term potentiation (LTP) via upregulation of the α-secretase (ADAM10) and the calcium signaling molecule PLCB4. Our findings suggest that synthetic biased agonists targeting CCKBR-Gq signaling have therapeutic potential for AD.

Keywords

Alzheimer's disease; CCKBR; PLC; biased agonists; cognitive enhancement; cryo-EM structure; inflammation; neuroprotection; structure-based drug design; synaptic plasticity.

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