MFG-E8调控小胶质细胞吞噬功能改善阿尔茨海默病的机制研究

Microglial (MG) phagocytosis plays a pivotal role in Alzheimer's Disease (AD). It is the potential therapeutic strategy for AD to inhibit microglial phagocytosis of neurons and to promote the clearance of Aβ. Our preliminary data indicated that MG treated with MFG-E8 in high concentration showed the decreased phagocytosis of neurons and the increased clearance of Aβ; the reversed changes were seen when cells were incubated with low level of this molecule. Subsequent study demonstrated that the down-regulation of MerTK (Neuron phagocytosis receptor) and the up-regulation of SCARA-1 (Aβ phagocytosis receptor) were observed with MFG-E8 exposure. Thus, we believe that MFG-E8 could be an ideal target to regulate microglial phagocytosis: it down-regulates MerTK to inhibit the phagocytosis of neurons, and up-regulates SCARA-1 to promote the phagocytosis of Aβ. This project would make clear the alteration phases of microglial phagocytosis of neurons and Aβ in vitro and in vivo. Microglial phagocytic changes of neurons and Aβ would be examined when MFG-E8 was modulated. The underlyding mechanisms of MFG-E8 on MerTK and SCARA-1 would also be tested. This study would study in multidimensional angles from animal, cell to molecule, and clarify the nervous microenvironmental changes in microglial phagocytosis of neurons and Aβ, providing the new breakthrough for AD treatment.

小胶质细胞（MG）吞噬在阿尔茨海默病（AD）中发挥重要作用。抑制MG吞噬神经元，促进其吞噬Aβ，是AD潜在治疗策略，如何调控值得研究。我们前期研究提示，高浓度MFG-E8引起MG吞噬神经元减少，吞噬Aβ增多；低浓度引起相反变化。MFG-E8处理下调MG MerTK（神经元吞噬受体），上调SCARA-1（Aβ吞噬受体）。因此，我们认为，MFG-E8可作为调控MG吞噬的理想位点：下调MerTK抑制吞噬神经元，上调SCARA-1促进吞噬Aβ。本课题拟：①明确在体及离体水平，MG吞噬Aβ和神经元变化时相；②以干扰及过表达技术，调节MFG-E8表达，观察对MG吞噬神经元和Aβ的作用；③探讨MFG-E8下调MerTK和上调SCARA-1的机制。本研究从动物、细胞到分子水平多维度进行研究，阐明MG吞噬神经元和Aβ的神经微环境变化，为AD的治疗提供新的突破口。

小胶质细胞（MG）吞噬在阿尔茨海默病（AD）中发挥重要作用。抑制MG吞噬神经元，促进其吞噬Aβ，是AD潜在治疗策略，如何调控值得研究。我们前期发现，AD患者脑组织MFG-E8表达减低。MFG-E8是调控MG吞噬功能的关键分子。本课题后重点探讨MFG-E8调控MG吞噬功能介导AD发病的潜在机制。本课题主要研究内容包括：①在体及离体水平，MG吞噬变化时相；②观察调节MFG-E8水平对MG吞噬功能的作用；③探讨MFG-E8对MerTK和SCARA-1的调控机制。我们研究发现：1. Aβ42刺激MG后，可引起吞噬神经元增多，而吞噬Aβ42则显著减少，而MFG-E8可逆转前述Aβ42的作用，引起MG吞噬Aβ42增多，吞噬神经元减少。2.MFG-E8可下调MerTK，上调SCARA-1表达，并有效抑制神经炎症过程中的氧化应激反应。3.MFG-E8可通过下调NF-kB，上调PI3K-Akt通路调控星形胶质细胞A1/A2亚型转化平衡。科学意义：本项目阐明MFG-E8通过对MerTK和SCARA-1的调控改善小胶质细胞吞噬功能，并有效调控MG氧化应激反应，及对星形胶质细胞A1/A2亚型转化的调节作用，指明了MFG-E8在AD中的潜在治疗作用，可作为AD治疗新的突破口。