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 

机构地区：[1]Department of Neurology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,210008,China [2]Department of Neurology,Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing,210008,China [3]Department of Neurology,Drum Tower Hospital of Nanjing Medical University,Nanjing,210008,China [4]Jiangsu Key Laboratory for Molecular Medicine,Medical School of Nanjing University,Nanjing,210008,China [5]Jiangsu Provincial Key Discipline of Neurology,Nanjing,210008,China

出　　处：《Neuroscience Bulletin》2024年第4期483-499,共17页神经科学通报（英文版）

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

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.

关 键 词：White matter injury Cognitive dysfunction MFG-E8 REMYELINATION Microglial phagocytosis 

分 类 号：R744.5[医药卫生—神经病学与精神病学]