Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier
Clearance of Alzheimer's amyloid-β1-40 peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier
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DOI：
10.1172/jci10498
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发表时间：
2000-12-01
影响因子：
15.9
通讯作者：
Zlokovic, BV
中科院分区：
文献类型：
--
作者：
Shibata, M;Yamada, S;Zlokovic, BV
人们对淀粉样β肽（A β）从大脑中的消除知之甚少。在年轻小鼠脑内微量注射后，I-125-A β（1.40）迅速从脑中清除（t（1/2）小于或等于25分钟），主要是通过血脑屏障（BBB）的血管转运。BBB处A β（1.40）的外排转运系统在15.3 nM时达到半饱和，在70 nM至100 nM之间达到最大转运能力。受体相关蛋白、抗LDL受体相关蛋白-1（LRP-1）和α 2-巨球蛋白（α M-2）的抗体显著抑制β（1.40）清除率。与成年野生型小鼠相比，年轻和老年载脂蛋白E（apoE）敲除小鼠以及老年野生型小鼠的清除率显著降低。没有证据表明A β在脑间质液中代谢，并在其穿过BBB进入循环之前降解为较小的肽片段和氨基酸。LRP-1虽然在年轻小鼠的脑微血管中丰富，但在老年动物中下调，并且这种下调与阿尔茨海默病（AD）患者脑中的区域A β积累相关。我们的结论是，血脑屏障从大脑中删除A β主要是通过年龄依赖性，LRP-1介导的运输，受α M-2和/或apoE的影响，并可能在AD受损。
Elimination of amyloid-beta peptide (A beta) from the brain is poorly understood. After intracerebral microinjections in young mice,I-125-A beta (1.40) was rapidly removed from the brain (t(1/2) less than or equal to 25 minutes), mainly by vascular transport across the blood-brain barrier (BBB). The efflux transport system for A beta (1.40) at the BBB was half saturated at 15.3 nM, and the maximal transport capacity was reached between 70 nM and 100 nM. A beta (1.40) clearance was substantially inhibited by the receptor-associated protein, and by antibodies against LDL receptor-related protein-1 (LRP-1) and alpha (2)-macroglobulin (alpha M-2), As compared to adult wild-type mice, clearance was significantly reduced in young and old apolipoprotein E (apoE) knockout mice, and in old wild-type mice. There was no evidence that A beta was metabolized in brain interstitial fluid and degraded to smaller peptide fragments and amino acids before its transport across the BBB into the circulation. LRP-1, although abundant in brain microvessels in young mice, was downregulated in older animals, and this downregulation correlated with regional A beta accumulation in brains of Alzheimer's disease (AD) patients. We conclude that the BBB removes A beta from the brain largely via age-dependent, LRP-1-mediated transport that is influenced by alpha M-2 and/or apoE, and may be impaired in AD.