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Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease

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Abstract

Synaptic impairment and loss are an important pathological feature of Alzheimer's disease (AD). Memory is stored in neural networks through changes in synaptic activity, and synaptic dysfunction can cause cognitive dysfunction and memory loss. Cholecystokinin (CCK) is one of the major neuropeptides in the brain, and plays a role as a neurotransmitter and growth factor. The level of CCK in the cerebrospinal fluid is decreased in AD patients. In this study, a novel CCK analogue was synthesized on the basis of preserving the minimum bioactive fragment of endogenous CCK to investigate whether the novel CCK analogue could improve synaptic plasticity in the hippocampus of the APP/PS1 transgenic mouse model of AD and its possible molecular biological mechanism. Our study found that the CCK analogue could effectively improve spatial learning and memory, enhance synaptic plasticity in the hippocampus, normalize synapse numbers and morphology and the levels of key synaptic proteins, up-regulate the PI3K/Akt signaling pathway and normalize PKA, CREB, BDNF and TrkB receptor levels in APP/PS1 mice. The amyloid plaque load in the brain was reduced by CCK, too. The use of a CCKB receptor antagonist and targeted knockdown of the CCKB receptor (CCKBR) attenuated the neuroprotective effect of the CCK analogue. These results demonstrate that the neuroprotective effect of CCK analogue is achieved by activating the PI3K/Akt as well as the PKA/CREB-BDNF/TrkB signaling pathway that leads to protection of synapses and cognition.

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Data Availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

This article does not contain any studies with human participants performed by any of the authors.

Abbreviations

AD:

Alzheimer’s disease

Aβ:

Amyloid β-protein

APP:

Amyloid precursor protein

PS1:

Presenilin-1

CCK:

Cholecystokinin

CCKAR:

Cholecystokinin A receptor

CCKBR:

Cholecystokinin B receptor

CCKR:

Cholecystokinin B receptor

PI3K:

Phosphatidylinositol 3-kinase

AKT:

Protein kinase B

PKA:

Protein kinase A

CREB:

CAMP-response element binding protein

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tyrosine Kinase receptor B

MAP-2:

Microtubule associated protein 2

PSD95:

Postsynaptic density95

Syn:

Synapsin

NMDAR:

N-methyl-D-aspartate receptor

LTP:

Long-term potentiation

fEPSP:

Field excitatory postsynaptic potential

TEM:

Transmission electron microscopy

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Acknowledgements

We thank researcher Ning-Sun, Researcher Xiang-hua Liu, and Researcher Cai-Li Zhang for TEM technical assistance.

Funding

This work was supported by Natural Science Foundation of China(U1504829), Doctoral Fund of Henan University of Chinese Medicine (numbers BSJJ2022-09), Scientific and Technological Innovation Team Support Program for Colleges and Universities in Henan Province (21IRTSTHN026), Joint Research Fund of Science and Technology R&D Plan of Henan Province (NO. 222301420068).

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Authors and Affiliations

  1. School of Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China

    Zijuan Zhang, Ziyang Yu & Li Hao

  2. Academy of Chinese Medical Sciences, Henan Engineering Research Center for Prevention and Treatment of Major Chronic Diseases With Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, 450046, Henan Province, China

    Ye Yuan, Jing Yang, Shijie Wang, He Ma, Jinlian Ma, Zhonghua Li, Zhenqiang Zhang & Christian Hölscher

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Contributions

Zijuan Zhang: Writing-original draft, Conceptualization. Ziyang Yu: Software, Investigation, Data curation. Ye Yuan: Data curation. Jing Yang: Formal analysis. Shijie Wang: Project administration. He Ma: Formal analysis. Li Hao: Investigation. Zhonghua Li: Investigation. Zhenqiang Zhang: Supervision, Funding acquisition. Christian Hölscher: Editing, Supervision, Funding acquisition.

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Correspondence to Zhenqiang Zhang or Christian Hölscher.

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All animals were treated according to the guidelines for the Care and Use of Laboratory Animals and the experimental procedures were approved by the Animal Care and Use Committee of Henan University of Chinese Medicine (No: DWLL201903076).

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Zhang, Z., Yu, Z., Yuan, Y. et al. Cholecystokinin Signaling can Rescue Cognition and Synaptic Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 60, 5067–5089 (2023). https://doi.org/10.1007/s12035-023-03388-7

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