Shackleton B, Crawford F, Bachmeier C
The Roskamp Institute, Sarasota, FL, 34243, USA.
The Open University, Milton Keynes, Buckinghamshire, MK7 6AA, UK.
Fluids Barriers CNS. 2016 Aug 8;13(1):14. doi: 10.1186/s12987-016-0038-x.
Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One of the receptors responsible for the transport of Aβ in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Aβ transit across the BBB. Several proteases contribute to the ectodomain shedding of LRP1 including the α-secretase, a desintegrin and metalloproteinase domain containing protein 10 (ADAM10).
The role of ADAM10 in the shedding of LRP1 and Aβ BBB clearance was assessed through pharmacological inhibition of ADAM10 in an in vitro model of the BBB and through the use of ADAM10 endothelial specific knock-out mice. In addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and Aβbrain accumulation.
In the current studies, inhibition of ADAM10 reduced LRP1 shedding in brain endothelial cultures and increased Aβ42 transit across an in vitro model of the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Aβ clearance across the BBB compared to wild-type animals. Acute treatment with the ADAM10-selective inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1 shedding and increased Aβ40 levels in the plasma, indicating enhanced Aβ transit from the brain to the periphery. Furthermore, both soluble and insoluble Aβ40 and Aβ42 brain levels were decreased following GI254023X treatment, but these effects lacked statistical significance.
These studies demonstrate a role for ADAM10 in the ectodomain shedding of LRP1 in the brain and the clearance of Aβ across the BBB, which may provide a novel strategy for attenuating Aβ accumulation in the AD brain.
跨血脑屏障（BBB）的转运是β-淀粉样蛋白（Aβ）在脑内蓄积的重要介导因素，也是阿尔茨海默病（AD）发病机制的一个促成因素。血脑屏障中负责转运Aβ的受体之一是低密度脂蛋白受体相关蛋白1（LRP1）。LRP1在细胞表面易受蛋白水解性裂解，这会阻止配体的内吞转运。此前，我们报道了脑内LRP1的裂解与Aβ跨血脑屏障转运之间存在强烈的负相关。几种蛋白酶参与了LRP1的胞外域裂解，包括α-分泌酶、含去整合素和金属蛋白酶结构域蛋白10（ADAM10）。
通过在血脑屏障体外模型中对ADAM10进行药理学抑制以及使用ADAM10内皮细胞特异性敲除小鼠，评估ADAM10在LRP1裂解和Aβ血脑屏障清除中的作用。此外，还在AD小鼠模型中测试了ADAM10抑制剂的急性治疗模式，以评估ADAM10抑制对LRP1裂解和Aβ脑内蓄积的影响。
在当前研究中，抑制ADAM10可减少脑内皮细胞培养物中LRP1的裂解，并增加Aβ42跨血脑屏障体外模型的转运。同样，转基因ADAM10内皮细胞敲除小鼠脑内LRP1的裂解较低，与野生型动物相比，其血脑屏障的Aβ清除显著增强。在AD小鼠模型中用ADAM10选择性抑制剂GI254023X进行急性治疗可大幅减少脑内LRP1的裂解，并增加血浆中Aβ40水平，表明Aβ从脑到外周的转运增强。此外，GI254023X治疗后，可溶性和不溶性Aβ40及Aβ42的脑内水平均降低，但这些效应缺乏统计学意义。
这些研究证明了ADAM10在脑内LRP1的胞外域裂解以及Aβ跨血脑屏障清除中的作用，这可能为减轻AD脑内Aβ蓄积提供一种新策略。
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