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

Jia-Le Wang; Xue-Ying Sha; Yue Shao; Zi-Hao Zhang; Shen-Ming Huang; Hui Lin; Shi-Yi Gan; Nan Zhang; Xin-Yi Xia; Yu-Nan Sun; Jin-Hui Ding; Rui-Qi Zhao; Jie Cheng; Pan Shang; Jin-Peng Wang; Yan-Jun Liu; Fan Yang; Peng Xiao; Lu-Wen Wang; Dong-Yu Zhao; Yi Tang; Lu Tie; Yang Du; Yong Zhang; Ju-Fang He; Jin-Peng Sun

doi:10.1016/j.cell.2025.10.034

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

Jia-Le Wang (Co-first Author)
, Xue-Ying Sha (Co-first Author)
, Yue Shao (Co-first Author)
, Zi-Hao Zhang (Co-first Author)
, Shen-Ming Huang (Co-first Author)
, Hui Lin (Co-first Author)
, Shi-Yi Gan (Co-first Author)
, Nan Zhang
, Xin-Yi Xia
, Yu-Nan Sun
, Jin-Hui Ding
, Rui-Qi Zhao
, Jie Cheng
, Pan Shang
, Jin-Peng Wang
, Yan-Jun Liu
, Fan Yang
, Peng Xiao
, Lu-Wen Wang
, Dong-Yu Zhao

Yi Tang^*, Lu Tie^*, Yang Du^*, Yong Zhang^*, Ju-Fang He^*, Jin-Peng Sun^*

^*Corresponding author for this work

Department of Neuroscience

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

47 Citations (Scopus)

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. © 2025 Elsevier Inc.

Original language	English
Pages (from-to)	640-658, e1-22
Number of pages	41
Journal	Cell
Volume	189
Issue number	2
Online published	20 Nov 2025
DOIs	https://doi.org/10.1016/j.cell.2025.10.034
Publication status	Published - 22 Jan 2026

Funding

This research was supported by funding from the National Science Fund for Distinguished Young Scholars of China (82425105 to J.-P.S.), the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (2024ZD0523100 to J.-P.S.), the National Key R&D Program of China (2024YFA0916900 to J.-P.S.), the National Natural Science Foundation of China (32130055, 32361163612, and 82330118 to J.-P.S.; 32271263 to Y.D.; 82220108009 to Y.T.; and 82304583 to H.L.), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (T2321004 to J.-P.S.), the International (Regional) Cooperation and Exchange Programs of the National Natural Science Foundation of China (3231101039 to J.-P.S.), the Unconventional Innovation Project of Beijing Natural Science Foundation (F251012 to J.-L.W.), Beijing Natural Science Foundation (Z200019 to J.-P.S. and L.T.), the National Natural Science Foundation of China (92168120 to L.T.), Science and Technology Innovation 2030 Major Projects (2022ZD0204900 to Y.Z.), Science and Technology Projects in Guangzhou (202102070001 to S.-M.H.), Collaborative Research Fund (CRF) of China, Hong Kong (C1002-24WF and C1043-21GF to J.-F.H.), the General Research Fund (GRF) of China, Hong Kong (11104524, 11102422, and 11104923 to J.-F.H.), Shenzhen Sci. & Technol. Innovation Bureau (JCYJ 20220818103009018 and JCYJ 20240813113521028 to Y.D.), InnoHK Centre for Regenerative Medicine and Health (to J.-F.H.), and Senior Research Fellow Scheme (SRFS) of China, Hong Kong (SRFS2324-1S02 to J.-F.H.). J.-P.S. is supported by the Tencent New Cornerstone Investigator Program.

Research Keywords

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

RGC Funding Information

RGC-funded

ESI Highly Cited Papers

Highly Cited Paper 2026

ESI Highly Cited Paper Designation Date(s)

20260709
20260923

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10.1016/j.cell.2025.10.034Licence: Elsevier user license

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Cite this

Wang, J.-L., Sha, X.-Y., Shao, Y., Zhang, Z.-H., Huang, S.-M., Lin, H., Gan, S.-Y., Zhang, N., Xia, X.-Y., Sun, Y.-N., Ding, J.-H., Zhao, R.-Q., Cheng, J., Shang, P., Wang, J.-P., Liu, Y.-J., Yang, F., Xiao, P., Wang, L.-W., ... Sun, J.-P. (2026). Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment. Cell, 189(2), 640-658, e1-22. https://doi.org/10.1016/j.cell.2025.10.034

@article{4f8825e9fdf9489fb48734b275525f74,

title = "Elucidating pathway-selective biased CCKBR agonism for Alzheimer{\textquoteright}s disease treatment",

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{\textquoteright}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. {\textcopyright} 2025 Elsevier Inc.",

keywords = "Alzheimer's disease, biased agonists, CCKBR, cognitive enhancement, cryo-EM structure, inflammation, neuroprotection, PLC, structure-based drug design, synaptic plasticity",

author = "Jia-Le Wang and Xue-Ying Sha and Yue Shao and Zi-Hao Zhang and Shen-Ming Huang and Hui Lin and Shi-Yi Gan and Nan Zhang and Xin-Yi Xia and Yu-Nan Sun and Jin-Hui Ding and Rui-Qi Zhao and Jie Cheng and Pan Shang and Jin-Peng Wang and Yan-Jun Liu and Fan Yang and Peng Xiao and Lu-Wen Wang and Dong-Yu Zhao and Yi Tang and Lu Tie and Yang Du and Yong Zhang and Ju-Fang He and Jin-Peng Sun",

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doi = "10.1016/j.cell.2025.10.034",

language = "English",

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Wang, J-L, Sha, X-Y, Shao, Y, Zhang, Z-H, Huang, S-M, Lin, H, Gan, S-Y, Zhang, N, Xia, X-Y, Sun, Y-N, Ding, J-H, Zhao, R-Q, Cheng, J, Shang, P, Wang, J-P, Liu, Y-J, Yang, F, Xiao, P, Wang, L-W, Zhao, D-Y, Tang, Y, Tie, L, Du, Y, Zhang, Y, He, J-F & Sun, J-P 2026, 'Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment', Cell, vol. 189, no. 2, pp. 640-658, e1-22. https://doi.org/10.1016/j.cell.2025.10.034

TY - JOUR

T1 - Elucidating pathway-selective biased CCKBR agonism for Alzheimer’s disease treatment

AU - Wang, Jia-Le

AU - Sha, Xue-Ying

AU - Shao, Yue

AU - Zhang, Zi-Hao

AU - Huang, Shen-Ming

AU - Lin, Hui

AU - Gan, Shi-Yi

AU - Zhang, Nan

AU - Xia, Xin-Yi

AU - Sun, Yu-Nan

AU - Ding, Jin-Hui

AU - Zhao, Rui-Qi

AU - Cheng, Jie

AU - Shang, Pan

AU - Wang, Jin-Peng

AU - Liu, Yan-Jun

AU - Yang, Fan

AU - Xiao, Peng

AU - Wang, Lu-Wen

AU - Zhao, Dong-Yu

AU - Tang, Yi

AU - Tie, Lu

AU - Du, Yang

AU - Zhang, Yong

AU - He, Ju-Fang

AU - Sun, Jin-Peng

PY - 2026/1/22

Y1 - 2026/1/22

N2 - 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. © 2025 Elsevier Inc.

AB - 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. © 2025 Elsevier Inc.

KW - Alzheimer's disease

KW - biased agonists

KW - CCKBR

KW - cognitive enhancement

KW - cryo-EM structure

KW - inflammation

KW - neuroprotection

KW - PLC

KW - structure-based drug design

KW - synaptic plasticity

UR - https://www.scopus.com/pages/publications/105025009052

UR - https://www.scopus.com/pages/publications/105025009052#tab=impact

U2 - 10.1016/j.cell.2025.10.034

DO - 10.1016/j.cell.2025.10.034

M3 - RGC 21 - Publication in refereed journal

C2 - 41270732

SN - 0092-8674

VL - 189

SP - 640-658, e1-22

JO - Cell

JF - Cell

IS - 2

ER -

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

Abstract

Funding

Research Keywords

RGC Funding Information

ESI Highly Cited Papers

ESI Highly Cited Paper Designation Date(s)

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Permanent Link

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GRF: Roles of Cholecystokinin in The Plasticity of Gabaergic and Glutamatergic Synapses in The Basolateral Amygdala

GRF: Cholecystokinin from the Thalamocortical Projection Facilitates Heterosynaptic Visual Inputs in the Auditory Cortex and Visuoauditory Association

SRFS: The Medial Prefrontal Cortex Facilitates Learning and Memory in the Auditory Cortex Through the Medial Temporal Lobe

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