AccScience Publishing / AN / Volume 2 / Issue 3 / DOI: 10.36922/an.0974
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ORIGINAL RESEARCH ARTICLE

Cognition damage due to disruption of cyclic adenosine monophosphate-related signaling pathway in melatonin receptor 2 knockout mice

He-Zhou Huang1† ,  Xiang Wang2† ,  Dan Liu3*
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1 Department of Pathophysiology, Key Laboratory of Neurological Disorders of the Education Ministry, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2 Department of Histology and Embryology, Medical College, Jianghan University, Wuhan, China
3 Department of Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Advanced Neurology 2023, 2(3), 0974 https://doi.org/10.36922/an.0974
Submitted: 22 May 2023 | Accepted: 13 July 2023 | Published: 11 August 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Alzheimer’s disease (AD) was characterized by the presence of neurofibrillary tangles and senile plaques. Although melatonin plays an important role in AD, its mechanism is still unknown. In this study, we found obvious cognition damage in melatonin receptor 2 knockout mice (MT2KO) and double knockout mice (DKO), but not in melatonin receptor 1 knockout mice (MT1KO). To explore the mechanism in-depth, we attempted to determine the levels of metabolites and amyloid-β peptide (Aβ). A high level of Cho/tCr (choline/total creatine) was detected in MT2KO and MT1KO by nuclear magnetic resonance (NMR), while a high level of myo-inositol/total creatine (mI/tCr) was only detected in MT1KO. A higher ratio of Aβ42/40 was found in MT2KO, but not in MT1KO and DKO. We also found an abnormal increase of plaque detected by the A3981 antibody in MT2KO and DKO. Furthermore, a huge decrease of postsynapses was confirmed in MT2KO and DKO, but not MT1KO, accompanied by a low level of phosphorylated cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) at the site of serine 133 and a low activity of protein kinase A. Finally, the cAMP, cyclic guanosine monophosphate, and cAMP-regulated guanine nucleotide exchange factor (EPAC) were detected. We observed a significant decrease of cAMP and EPAC2 in MT2KO, but not MT1KO. Thus, we identified that cAMP-related signaling pathway was disturbed in MT2KO and was critical for normal cognitive function.

Keywords
Melatonin receptor 2
Plaque
Cyclic adenosine monophosphate
cAMP response element-binding
Cognition
Funding
Brain Science and Brain-inspired Research
National Natural Science Foundation of China
Top-Notch Young Talents Program of China of 2014
Fundamental Research Funds for the Central Universities
Hubei Provincial Natural Science Foundation
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Conflict of interest
The authors declare that they have no competing financial interests in this paper.
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Advanced Neurology, Electronic ISSN: 2810-9619 Published by AccScience Publishing
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