脂蛋白E通过环素A控制大脑血管完整性
Robert D Bell1, Ethan A Winkler, Itender Singh
1Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA.
Nature
|May 25, 2012
概括
APOE4基因变异和Apoe蛋白质的缺失通过激活特定的炎症途径来破坏血脑屏障 (BBB). 这导致神经血管损伤和神经元功能障碍,建议治疗 APOE4 相关的神经退行症的目标.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 是一个遗传学.
- 血管生物学 血管生物学
背景情况:
- 人类阿波利波蛋白E (APOE) 有三种异型:APOE2,APOE3和APOE4.
- APOE4是阿尔茨海默病和其他神经系统疾病的重要遗传风险因素.
- 在APOE4携带者和相关疾病中观察到神经血管功能障碍,但潜在的机制尚不清楚.
研究的目的:
- 调查APOE基因型如何影响大脑微循环和血脑屏障 (BBB) 完整性.
- 阐明参与APOE4相关的神经血管功能障碍的分子途径.
主要方法:
- 利用了APOE转基因小鼠模型,包括那些对环素A (CypA) 进行基因操纵的模型.
- 研究了不同APOE异型和Apoe缺陷对BBB完整性和神经血管功能的影响.
- 研究了CypA-核因子-κB-矩阵-金属蛋白酶-9 (NF-κB-MMP9) 途径在皮细胞中的作用.
主要成果:
- 表达APOE4和缺乏小鼠Apoe,但不是APOE2或APOE3,导致BBB分解.
- 这种分解是通过激活皮质细胞中的一种促炎性CypA-NF-κB-MMP9通路来调节的.
- 血管缺陷,包括微血管和脑血流减少,先于神经元功能障碍并启动神经退行性变化.
- 与APOE4不同的是,由天体细胞分泌的APOE3通过脂蛋白受体抑制了这种途径.
结论:
- APOE4和Apoe缺陷通过皮细胞中的CypA-NF-κB-MMP9通路诱导BBB分解,导致神经血管损伤.
- 这些血管缺陷先于并可以启动神经退行过程.
- 环素A (CypA) 被确定为缓解APOE4介导的神经血管损伤和随后的神经元功能障碍的关键治疗标.
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