Microglia-Derived Vitamin D Binding Protein Mediates Synaptic Damage and Induces Depression by Binding to the Neuronal Receptor Megalin.

Autor: Kong Y; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China.; Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China., Zhang X; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Li L; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Zhao T; Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China., Huang Z; Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China., Zhang A; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Sun Y; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Jiao J; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Zhang G; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China., Liu M; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China.; Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China., Han Y; Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China., Yang L; Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China., Zhang Z; Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease in Ministry of Education, Southeast University, Nanjing, 210096, China.; Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Dec 23, pp. e2410273. Date of Electronic Publication: 2024 Dec 23.
DOI: 10.1002/advs.202410273
Abstrakt: Vitamin D binding protein (VDBP) is a potential biomarker of major depressive disorder (MDD). This study demonstrates for the first time that VDBP is highly expressed in core emotion-related brain regions of mice susceptible to chronic unpredictable mild stress (CUMS). Specifically, the overexpression of microglia (MG)-derived VDBP in the prelimbic leads to depression-like behavior and aggravates CUMS-induced depressive phenotypes in mice, whereas conditional knockout of MG-derived VDBP can reverse both neuronal damage and depression-like behaviors. Mechanistically, the binding of MG-derived VDBP with the neuronal receptor megalin mediates the downstream SRC signaling pathway, leading to neuronal and synaptic damage and depression-like behaviors. These events may be caused by biased activation of inhibitory neurons and excitatory-inhibitory imbalance. Importantly, this study has effectively identified MG-derived VDBP as a pivotal mediator in the interplay between microglia and neurons via its interaction with the neuronal receptor megalin and intricate downstream impacts on neuronal functions, thus offering a promising therapeutic target for MDD.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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