肝脏X受体α通过抑制SNAI2确保了血脑屏障的功能
D Vacondio1,2, H Nogueira Pinto1,2, L Coenen1,2,3
1Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, De Boelelaan 1108, Amsterdam, the Netherlands.
Cell death & disease
|November 28, 2023
概括
肝X受体α (LXRα) 通过抑制SNAI2.2,从而保持血脑屏障 (BBB) 的完整性. 它在阿尔茨海默氏症 (AD) 与毛细血管大脑粉样血管病变 (capCAA) 的降低促进了BBB功能障碍和异常血管生成.
科学领域:
- 神经科学是一个神经科学.
- 血管生物学 血管生物学
- 分子生物学分子生物学
背景情况:
- 阿尔茨海默病 (AD) 通常涉及毛细血管大脑粉样血管病变 (capCAA),导致缺氧,神经炎症和血脑屏障 (BBB) 功能障碍.
- 阿尔茨海默病患者表现出血管形成的增加,这表明血管生成被重新激活,但潜在的分子机制仍然不清楚.
- 已知肝X受体 (LXR) 家族,特别是LXRα,可以抑制血管生成并保持BBB的稳定性.
研究的目的:
- 阐明LXRα在人类大脑内皮细胞 (BEC) 中维护BBB完整性的调节机制.
- 为了研究LXRα在诸如capCAA和缺氧等病理状况中的作用.
- 探索LXRα,SNAI2和AD中的血管变化之间的关联.
主要方法:
- 研究了LXRα在抑制人类BECs中的SNAI2中的作用.
- 研究了LXRα删除对BEC中DLL4-NOTCH信号的影响.
- 分析了AD患者带有和没有capCAA的脑后皮层中的血管SNAI2表达,将其与粉样蛋白-β和缺氧标志物相关联.
主要成果:
- LXRα构成性地抑制转录因子SNAI2,确保BEC的身份和BBB的完整性.
- 删除LXRα或缺氧导致LXRα降低,SNAI2增加,DLL4-NOTCH信号受损,以及BEC脱差/发芽.
- 血管SNAI2在患有capCAA的AD患者中升高,与粉样β沉积和血管类4 (低氧标志物) 相相关.
结论:
- LXRα对于保持BEC身份,BBB稳定性和防止异常血管生成至关重要.
- 在capCAA血管中缺氧期间LXRα的减少可能会导致SNAI2上调,导致BBB功能障碍和发芽.
- 这项研究揭示了一种新的LXRα-SNAI2通路,该通路对于AD的血管平衡至关重要.
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