ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage
ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage
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DOI：
10.1152/ajpcell.00563.2005
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Wagner, Denisa D.
中科院分区：
文献类型：
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作者：
Hafezi-Moghadam, Ali;Thomas, Kennard L.;Wagner, Denisa D.
此前，我们报道了载脂蛋白E缺陷(apoE(-/-))小鼠的血脑屏障(BBB)缺陷(24例)。在这里，我们研究了野生型(WT)和载脂蛋白E(-/-)小鼠的血脑屏障通透性随年龄的变化。WT和apoE(-/-)小鼠的皮质血脑屏障漏出量均随年龄增加而显著增加。然而，在apoE(-/-)小鼠中，渗漏增加的速度是WT小鼠的3.7倍。令人惊讶的是，小脑在不同年龄段表现出明显比其他大脑区域更多的渗漏，而两个半球之间没有差异。为了确定组织载脂蛋白E与血液载脂蛋白E对血管通透性的贡献，我们通过骨髓移植产生了嵌合小鼠，并测量了它们的血脑屏障渗漏。这些实验表明，血液和组织来源的载脂蛋白E对血脑屏障功能同样重要。总之，我们在载脂蛋白E(-/-)小鼠的血脑屏障中发现了一种年龄相关的缺陷，这种缺陷会加剧。由于在阿尔茨海默病等与年龄相关的神经退行性疾病患者中发现了血管缺陷，与年龄相关的血脑屏障渗漏可能是这些缺陷的基础，因此可能是这些疾病累积神经元损伤的重要因素。
Previously, we reported a defect in the blood-brain barrier ( BBB) of apolipoprotein E-deficient ( apoE(-/-)) mice ( 24). Here, we investigate BBB permeability in wild- type ( WT) and apoE(-/-) mice as a function of age. Both WT and apoE(-/-) mice showed significantly increased cortical BBB leakage with age. However, in apoE(-/-) mice, the leakage increased at a 3.7 x higher rate compared with WT mice. Surprisingly, the cerebellum showed significantly more leakage than other brain regions across age, while there was no difference between the two hemispheres. To determine the contribution of tissue- vs. blood- borne apoE to vascular permeability, we generated chimeric mice by bone marrow transplantation and measured their BBB leakage. These experiments suggest that both blood- and tissue- derived apoE are equally important for BBB function. In sum, we find an age-dependent defect in the BBB that is exacerbated in apoE(-/-) mice. Since vascular defects are found in patients with age- related neurodegenerative diseases, such as Alzheimer's, age- related BBB leakage could underlie these defects and may thus be an important contributor to the cumulative neuronal damage of these diseases.