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

Jia-Le Wang¹, Xue-Ying Sha², Yue Shao³, Zi-Hao Zhang⁴, Shen-Ming Huang⁵, Hui Lin⁶, Shi-Yi Gan⁷, Nan Zhang³, Xin-Yi Xia⁸, Yu-Nan Sun⁹, Jin-Hui Ding¹⁰, Rui-Qi Zhao¹¹, Jie Cheng¹², Pan Shang¹³, Jin-Peng Wang¹⁴, Yan-Jun Liu¹⁰, Fan Yang¹⁵, Peng Xiao¹⁶, Lu-Wen Wang¹⁷, Dong-Yu Zhao⁹, Yi Tang¹⁸, Lu Tie¹⁹, Yang Du²⁰, Yong Zhang²¹, Ju-Fang He²², Jin-Peng Sun²³

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: tangyi@xwhosp.org.
¹⁹ Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address: tielu@bjmu.edu.cn.
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: yangdu@cuhk.edu.cn.
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: yongzhang@hsc.pku.edu.cn.
²² Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China. Electronic address: jufanghe@cityu.edu.hk.
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: sunjinpeng@sdu.edu.cn.

PMID: 41270732
DOI: 10.1016/j.cell.2025.10.034

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

Jia-Le Wang et al. Cell. 2025.

. 2025 Nov 20:S0092-8674(25)01238-3.

doi: 10.1016/j.cell.2025.10.034. Online ahead of print.

Authors

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: tangyi@xwhosp.org.
¹⁹ Department of Pharmacology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China. Electronic address: tielu@bjmu.edu.cn.
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: yangdu@cuhk.edu.cn.
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: yongzhang@hsc.pku.edu.cn.
²² Department of Neuroscience, City University of Hong Kong, Kowloon Tong, Hong Kong, China. Electronic address: jufanghe@cityu.edu.hk.
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: sunjinpeng@sdu.edu.cn.

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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Declaration of interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

LinkOut - more resources

Full Text Sources