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 α_Vβ₃/α_Vβ₅/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.

慢性脑灌注不足是通过引起白质损伤导致认知能力下降的病理生理机制之一。小胶质细胞及时吞噬髓鞘碎片可以促进髓鞘再生，有助于白质的修复。然而，乳脂肪球-表皮生长因子-因子8（MFG-E8），一种小胶质细胞吞噬作用相关蛋白，在低灌注相关的认知功能障碍中尚未得到充分研究。我们发现双侧颈动脉狭窄（BCAS）后小鼠大脑中MFG-E8的表达显着降低。MFG-E8 基因敲除小鼠在行为测试中表现出更严重的 BCAS 诱导的认知障碍。此外，我们通过荧光染色和电镜发现MFG-E8的缺失加剧了白质损伤和髓磷脂微结构的破坏。同时，AAV 过度表达 MFG-E8 改善了 BCAS 后白质损伤并增加了成熟少突胶质细胞的数量。此外，体外和体内实验表明，MFG-E8可以通过αVβ3/αVβ5/Rac1途径增强小胶质细胞的吞噬功能和_IGF - _1的产生，促进少突胶质祖细胞向成熟少突胶质细胞的_分化。有趣的是，我们发现MFG-E8主要来源于星形胶质细胞，而不是小胶质细胞。我们的研究结果表明 MFG-E8 是脑灌注不足后认知障碍的潜在治疗靶点。