The Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL, 34243, USA.
The Open University, Milton Keynes, UK.
Mol Neurobiol. 2019 Dec;56(12):8296-8305. doi: 10.1007/s12035-019-01672-z. Epub 2019 Jun 18.
Lipoprotein receptor transport across the blood-brain barrier (BBB) mediates beta-amyloid (Aβ) accumulation in the brain and may be a contributing factor in Alzheimer's disease (AD) pathogenesis. Lipoprotein receptors are susceptible to proteolytic shedding at the cell surface, which precludes the endocytic transport of ligands. A ligand that closely interacts with the lipoprotein receptors is apolipoprotein E (apoE), which exists as three isoforms (apoE2, apoE3, apoE4). Our prior work showed an inverse relationship between lipoprotein receptor shedding and Aβ transport across the BBB, which was apoE-isoform dependent. To interrogate this further, the current studies investigated an enzyme implicated in lipoprotein receptor shedding, matrix metalloproteinase 9 (MMP9). Treatment with MMP9 dose-dependently elevated lipoprotein receptor shedding in brain endothelial cells and freshly isolated mouse cerebrovessels. Furthermore, treatment with a MMP9 inhibitor (SB-3CT) mitigated Aβ-induced lipoprotein receptor shedding in brain endothelial cells and the brains of apoE4 animals. In terms of BBB transit, SB-3CT treatment increased the transport of Aβ across an in vitro model of the BBB. In vivo, administration of SB-3CT to apoE4 animals significantly enhanced Aβ clearance from the brain to the periphery following intracranial administration of Aβ. The current studies show that MMP9 impacts lipoprotein receptor shedding and Aβ transit across the BBB, in an apoE isoform-specific manner. In total, MMP9 inhibition can facilitate Aβ clearance across the BBB, which could be an effective approach to lowering Aβ levels in the brain and mitigating the AD phenotype, particularly in subjects carrying the apoE4 allele.
载脂蛋白受体在血脑屏障（BBB）中的转运介导了β-淀粉样蛋白（Aβ）在大脑中的积累，可能是阿尔茨海默病（AD）发病机制的一个促成因素。载脂蛋白受体在细胞表面易发生蛋白水解脱落，从而阻止配体的内吞转运。一种与载脂蛋白受体密切相互作用的配体是载脂蛋白 E（apoE），它有三种异构体（apoE2、apoE3、apoE4）。我们之前的工作表明，载脂蛋白受体脱落与 Aβ 穿过 BBB 的转运呈负相关，这与 apoE 异构体依赖性有关。为了进一步研究这一点，目前的研究调查了一种与载脂蛋白受体脱落有关的酶，即基质金属蛋白酶 9（MMP9）。MMP9 的剂量依赖性处理可增加脑内皮细胞和新鲜分离的小鼠脑血管中的载脂蛋白受体脱落。此外，用 MMP9 抑制剂（SB-3CT）处理可减轻 Aβ 诱导的脑内皮细胞和 apoE4 动物大脑中的载脂蛋白受体脱落。就 BBB 转运而言，SB-3CT 处理可增加体外 BBB 模型中 Aβ 的转运。在体内，给予 apoE4 动物 SB-3CT 可显著增强 Aβ 从大脑到外周的清除率，方法是在颅内给予 Aβ。目前的研究表明，MMP9 以 apoE 异构体特异性的方式影响载脂蛋白受体脱落和 Aβ 通过 BBB 的转运。总的来说，MMP9 抑制可以促进 Aβ 通过 BBB 的清除，这可能是降低大脑中 Aβ 水平和减轻 AD 表型的有效方法，特别是在携带 apoE4 等位基因的患者中。
