Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice

Nan Zhang; Yixuan Sui; Peter Jendrichovsky; Hemin Feng; Heng Shi; Xu Zhang; Shenghui Xu; Wenjian Sun; Huatang Zhang; Xi Chen; Micky D. Tortorella; Jufang He

doi:10.1186/s13195-024-01472-1

Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice

Nan Zhang
, Yixuan Sui
, Peter Jendrichovsky
, Hemin Feng
, Heng Shi
, Xu Zhang
, Shenghui Xu
, Wenjian Sun
, Huatang Zhang
, Xi Chen
, Micky D. Tortorella^* (Co-last Author)
, Jufang He^* (Co-last Author)

^*Corresponding author for this work

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

13 Citations (Scopus)

127 Downloads (CityUHK Scholars)

Abstract

Background As one major symptom of Alzheimer’s disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD.

Methods mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK^−/−) mice. Animals’ cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation.

Results Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK^−/− mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists.

Conclusions Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Original language	English
Article number	109
Journal	Alzheimer's Research & Therapy
Volume	16
Online published	15 May 2024
DOIs	https://doi.org/10.1186/s13195-024-01472-1
Publication status	Published - 2024

Funding

This work was supported by funding from the following: Hong Kong Research Grants Council, General Research Fund: 11101521, 11103922, 11104923; Hong Kong Research Grants Council, Collaborative Research Fund: C1043-21G; Hong Kong Research Grants Council, Theme-Based Research Scheme: T13-605/18-W; Innovation and Technology Fund of the Hong Kong SAR, China: GHP_075_19GD; Hong Kong Research Grants Council, Senior Research Fellow Scheme: SRFS2324-1S02; Hong Kong Health Bureau, Health and Medical Research Fund: 08194106, 09203656; Innovation Technology Commission of the Hong Kong SAR, China: Health@InnoHK program. We also thank the following charitable foundations for their generous support to J.H: Wong Chun Hong Endowed Chair Professorship, Charlie Lee Charitable Foundation, and Fong Shu Fook Tong Foundation.

Research Keywords

Cholecystokinin
Cholecystokinin B receptor agonist
Anterograde amnesia
Alzheimer’s disease
HT-267

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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RGC-funded

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@article{c5923c027fa64f0cb078cc6588db8a3d,

title = "Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice",

abstract = "Background As one major symptom of Alzheimer{\textquoteright}s disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. Methods mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK−/−) mice. Animals{\textquoteright} cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. Results Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK−/− mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. Conclusions Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia. {\textcopyright} The Author(s) 2024.",

keywords = "Cholecystokinin, Cholecystokinin B receptor agonist, Anterograde amnesia, Alzheimer{\textquoteright}s disease, HT-267",

author = "Nan Zhang and Yixuan Sui and Peter Jendrichovsky and Hemin Feng and Heng Shi and Xu Zhang and Shenghui Xu and Wenjian Sun and Huatang Zhang and Xi Chen and Tortorella, \{Micky D.\} and Jufang He",

year = "2024",

doi = "10.1186/s13195-024-01472-1",

language = "English",

volume = "16",

journal = "Alzheimer's Research \& Therapy",

issn = "1758-9193",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice

AU - Zhang, Nan

AU - Sui, Yixuan

AU - Jendrichovsky, Peter

AU - Feng, Hemin

AU - Shi, Heng

AU - Zhang, Xu

AU - Xu, Shenghui

AU - Sun, Wenjian

AU - Zhang, Huatang

AU - Chen, Xi

AU - Tortorella, Micky D.

AU - He, Jufang

PY - 2024

Y1 - 2024

N2 - Background As one major symptom of Alzheimer’s disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. Methods mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK−/−) mice. Animals’ cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. Results Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK−/− mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. Conclusions Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia. © The Author(s) 2024.

AB - Background As one major symptom of Alzheimer’s disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. Methods mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK−/−) mice. Animals’ cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. Results Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK−/− mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. Conclusions Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia. © The Author(s) 2024.

KW - Cholecystokinin

KW - Cholecystokinin B receptor agonist

KW - Anterograde amnesia

KW - Alzheimer’s disease

KW - HT-267

UR - https://www.scopus.com/pages/publications/85193312997

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85193312997&origin=recordpage

U2 - 10.1186/s13195-024-01472-1

DO - 10.1186/s13195-024-01472-1

M3 - RGC 21 - Publication in refereed journal

C2 - 38750512

SN - 1758-9193

VL - 16

JO - Alzheimer's Research & Therapy

JF - Alzheimer's Research & Therapy

M1 - 109

ER -

Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice

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

GRF: Heterosynaptic Neuroplasticity of the Ascending Inputs in the Auditory Thalamus by Corticothalamic Modulation

HMRF: CCK-B Receptor Antagonist for the Treatment of Depression in the Mouse Model

Cite this

Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

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

GRF: Heterosynaptic Neuroplasticity of the Ascending Inputs in the Auditory Thalamus by Corticothalamic Modulation

HMRF: CCK-B Receptor Antagonist for the Treatment of Depression in the Mouse Model

Cite this