MFG-E8 Alleviates Cognitive Impairments Induced by Chronic Cerebral Hypoperfusion by Phagocytosing Myelin Debris and Promoting Remyelination

作     者：Xiaohong Dong Zhi Zhang Xin Shu Zi Zhuang Pinyi Liu Renyuan Liu Shengnan Xia Xinyu Bao Yun Xu Yan Chen 

作者机构：Department of NeurologyNanjing Drum Tower HospitalAffiliated Hospital of Medical SchoolNanjing UniversityNanjing210008China Department of NeurologyNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjing210008China Department of NeurologyDrum Tower Hospital of Nanjing Medical UniversityNanjing210008China Jiangsu Key Laboratory for Molecular MedicineMedical School of Nanjing UniversityNanjing210008China Jiangsu Provincial Key Discipline of NeurologyNanjing210008China 

出 版 物：《Neuroscience Bulletin》 (神经科学通报（英文版）)

年 卷 期：2024年第40卷第4期

页      面：483-499页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(81801147 and 81971112). 

主　　题：White matter injury Cognitive dysfunction MFG-E8 Remyelination Microglial phagocytosis 

摘      要：Chronic cerebral hypoperfusion is one of the pathophysiological mechanisms contributing to cognitive decline by causing white matter injury.Microglia phagocytosing myelin debris in a timely manner can promote remyelination and contribute to the repair of white matter.However,milk fat globule-epidermal growth factor-factor 8(MFG-E8),a microglial phagocytosis-related protein,has not been well studied in hypoperfusion-related cognitive dysfunction.We found that the expression of MFG-E8 was significantly decreased in the brain of mice after bilateral carotid artery stenosis(BCAS).MFG-E8 knockout mice demonstrated more severe BCAS-induced cognitive impairments in the behavioral tests.In addition,we discovered that the deletion of MFG-E8 aggravated white matter damage and the destruction of myelin microstructure through fluorescent staining and electron microscopy.Meanwhile,MFG-E8 overexpression by AAV improved white matter injury and increased the number of mature oligodendrocytes after BCAS.Moreover,in vitro and in vivo experiments showed that MFG-E8 could enhance the phagocytic function of microglia via theαVβ3/αVβ5/Rac1 pathway and IGF-1 production to promote the differentiation of oligodendrocyte progenitor cells into mature oligodendrocytes.Interestingly,we found that MFG-E8 was mainly derived from astrocytes,not microglia.Our findings suggest that MFG-E8 is a potential therapeutic target for cognitive impairments following cerebral hypoperfusion.