MOV10结合SNHG1和SCAMP1形成反馈环调控AD血脑屏障通透性和神经元凋亡的分子机制

Aβ induced vascular dysfunction and neuronal degeneration play crucial roles in the development of Alzheimer's disease (AD). However, the mechanism remains unclear. Our previous research found that MOV10, the RNA binding protein over-expressed in AD cerebral vascular endothelial cells and neuronal cells, could affect the BBB permeability and apoptosis of neuronal cells. The working hypothesis was established based on the results of screening and other studies. MOV10 over-expressed in AD down-regulates the expression of SNHG1 and SCAMP1 by binding with them. In addition, they negatively regulate the expression of FOSL2 and NFE2 via Polycomb Repressive Complex 2 (PRC2) pathway. Further analysis shows that the interaction between FOSL2 and NFE2 regulates the expression of downstream target gene ZnT1 and ZnT3, as well as the upstream MOV10, forming a feedback loop and resulting in increased BBB permeability and neuronal apoptosis. In the present study, we focus on three aspects: i) the mechanism of MOV10 regulating the expression of SNHG1 and SCAMP1; ii) the mechanism of SNHG1 and SCAMP1 reducing the expression of FOSL2 and NFE2 via the PRC2 pathway; iii) the interaction between FOSL2 and NFE2 and their targeted binding with ZnT1, ZnT3 and MOV10 in the regulatation of BBB permeability and neuronal apoptosis. The research aims to provide a new basis for the study of the pathogenesis and treatment of AD.

Aβ诱导血管功能紊乱和神经元变性在AD发生发展中起重要作用，但机制不清。我们发现AD脑血管内皮细胞和神经元中RNA结合蛋白MOV10高表达，影响BBB通透性和神经元凋亡。通过筛选等研究建立工作假说：AD中高表达的MOV10结合并下调SNHG1、SCAMP1的表达；二者通过PRC2复合体途径负性调节FOSL2和NFE2的表达；FOSL2和NFE2相互作用一方面调控下游ZnT1和ZnT3的表达，另一方面调控上游MOV10的表达，形成反馈环路，共同促进BBB通透性增加和神经元凋亡。本研究拟先明确MOV10调控SNHG1和SCAMP1的表达的机制；进一步研究SNHG1和SCAMP1通过PRC2途径下调FOSL2和NFE2的表达的机制；研究FOSL2和NFE2相互作用以及与ZnT1、ZnT3、MOV10的靶向结合作用对BBB通透性和神经元凋亡的作用机制。研究旨在为AD发病机制与治疗的研究提供新依据。

项目背景：Aβ诱导血管功能紊乱和神经元变性在AD发生发展中起重要作用，但机制不清。我们发现AD脑血管内皮细胞和神经元中RNA结合蛋白MOV10高表达，影响BBB通透性和神经元凋亡。.结果：1、MOV10在AD-ECs中高表达，敲减MOV10 显著降低了BBB通透性。2、SNHG1和SCAMP1在AD-ECs中低表达，敲减SNHG1 和SCAMP1显著增加了BBB通透性。3、敲减MOV10上调了AD-ECs中SNHG1 和SCAMP1的表达并增加了它们的稳定性。4、FOSL2和NFE2在AD-ECs中高表达，沉默FOSL2和NFE2降低了BBB的通透性。5、SNHG1和SCAMP1通过PRC2 复合体途径抑制FOSL2和NFE2的表达。6、FOSL2/NFE2可以结合ZnT1、ZnT3 和MOV10的启动子区并促进其表达，进一步形成反馈环路影响AD微环境下BBB 的通透性。.本研究首次证明了RNA结合蛋白MOV10、FOSL2、NFE2、ZnT1、ZnT3在AD-ECs中高表达，SNHG1、SCAMP1在AD-ECs中低表达。AD-ECs中MOV10结合SNHG1和SCAMP1，SNHG1和SCAMP1通过PRC2复合体途径结合FOSL2和NFE2抑制其表达，下调的FOSL2和NFE2通过在转录水平正性调控下游Zn T1和ZnT3及上游MOV10，降低AD微环境下BBB的通透性。.科学意义：因此，MOV10结合SNHG1和SCAMP1形成的反馈环路在调节AD微环境下BBB通透性中发挥着重要作用。本研究可为阿尔茨海默病的治疗提供新的靶点。