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

 Xiaohong Dong1,2 · Zhi Zhang1,2 · Xin Shu1,2 · Zi Zhuang3  · Pinyi Liu1,4,5 · Renyuan Liu1,4,5 · Shengnan Xia1,4,5 · Xinyu Bao1,4,5 · Yun Xu1,2,3,4,5  · Yan Chen1,4,5
1 Department of Neurology, Nanjing Drum Tower Hospital, Afliated 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

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 the αVβ3Vβ5/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.

White matter injury; Cognitive dysfunction; MFG-E8; Remyelination; Microglial phagocytosis