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PMID: 34617321 Published · ppublish English Journal Article

Melatonin ameliorates cognitive deficits through improving mitophagy in a mouse model of Alzheimer's disease.

Journal of pineal research ·Vol. 71 ·No. 4 ·2021-12-00 ·Pages e12774

Chen C, Yang C, Wang J, Huang X, Yu H, Li S, Li S, Zhang Z, Liu J, Yang X, Liu GP

Abstract

While melatonin is known to have protective effects in mitochondria-related diseases, aging, and neurodegenerative disorders, there is poor understanding of the effects of melatonin treatment on mitophagy in Alzheimer's disease (AD). We used proteomic analysis to investigate the effects and underlying molecular mechanisms of oral melatonin treatment on mitophagy in the hippocampus of 4-month-old wild-type mice versus age-matched 5 × FAD mice, an animal model of AD. 5 × FAD mice showed disordered mitophagy and mitochondrial dysfunction as revealed by increased mtDNA, mitochondrial marker proteins and MDA production, decreased electron transport chain proteins and ATP levels, and co-localization of Lamp1 and Tomm20. Melatonin treatment reversed the abnormal expression of proteins in the signaling pathway of lysosomes, pathologic phagocytosis of microglia, and mitochondrial energy metabolism. Moreover, melatonin restored mitophagy by improving mitophagosome-lysosome fusion via Mcoln1, and thus, ameliorated mitochondrial functions, attenuated Aβ pathology, and improved cognition. Concurrent treatment with chloroquine and melatonin blocked the positive behavioral and biochemical effects of administration with melatonin alone. Taken in concert, these results suggest that melatonin reduces AD-related deficits in mitophagy such that the drug should be considered as a therapeutic candidate for the treatment of AD.

Keywords
Alzheimer's disease melatonin mitochondrial function mitophagy proteomic
MeSH Terms
Alzheimer Disease/drug therapy Amyloid beta-Protein Precursor/genetics Animals Cognition Melatonin/pharmacology Mice Mitophagy Proteomics
Chemicals
Amyloid beta-Protein Precursor Melatonin
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Chen Chongyang
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yang Chao
Cognitive Impairment Ward of Neurology Department, the Third Affiliated Hospital of Shenzhen University Medical College, Shenzhen, Guangdong, China. | Department of Neurology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Wang Jing
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Huang Xi
Department of Neurology, Shenzhen People's Hospital (First Affiliated Hospital of Southern University of Science and Technology), Second Clinical College, Jinan University, Shenzhen, Guangdong Province, China.
Yu Haitao
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Li Shangming
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Li Shupeng ORCID
School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.
Zhang Zaijun
Institute of New Drug Research and Guangzhou, Key Laboratory of Innovative Chemical Drug Research in Cardio-cerebrovascular Diseases, Jinan University College of Pharmacy, Guangzhou, China.
Liu Jianjun
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Yang Xifei
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology (2020-2024), Shenzhen Center for Disease Control and Prevention, Shenzhen, China.
Liu Gong-Ping
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. | Co-innovation Center of Neurodegeneration, Nantong University, Nantong, JS, China.
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Article Info
Journal
Journal of pineal research
Abbr.
J Pineal Res
ISSN
1600-079X
DOI
10.1111/jpi.12774
Published
2021-12-00
Epub
2021-00-15
Pages
e12774
Language
English
Region
England
NLM ID
8504412
Subset
IM
Grants
Natural Science Foundation of China (81673134, 81870846)
the Ministry of Science and Technology of China (2016YFC13058001)
Key program of Shenzhen Basic Research (JCYJ20200108165353400)
Guangdong Provincial Key S&T Program (2018B030336001)
Sanming Project of Medicine in Shenzhen (SZSM201611090)
External Links
PubMed source DOI: 10.1111/jpi.12774 View journal details
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