Halliday Matthew R, Rege Sanket V, Ma Qingyi, Zhao Zhen, Miller Carol A, Winkler Ethan A, Zlokovic Berislav V
J Cereb Blood Flow Metab. 2016 Jan;36(1):216-27. doi: 10.1038/jcbfm.2015.44.
The blood–brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer’s disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA–MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.
血脑屏障（BBB）限制神经毒性血液衍生产物和细胞进入大脑，这对于正常神经元功能和信息处理是必需的。周细胞维持血脑屏障的完整性，并在阿尔茨海默病（AD）中退化。血脑屏障在AD中受损，尤其是在携带载脂蛋白E4（APOE4）基因的个体中，该基因是晚发性AD的主要遗传风险因素。然而，AD中血脑屏障破坏的潜在机制仍然难以捉摸。在这里，我们发现AD APOE4携带者>AD APOE3携带者>非AD对照组的周细胞加速退化，这与血脑屏障对免疫球蛋白G和纤维蛋白的破坏程度相关。我们还发现促炎细胞因子亲环素A（CypA）和基质金属蛋白酶-9（MMP-9）在AD（APOE4>APOE3）的周细胞和内皮细胞中积累，先前已证明这会导致转基因APOE4小鼠的血脑屏障破坏。AD APOE4和APOE3携带者中载脂蛋白E脂蛋白受体、低密度脂蛋白受体相关蛋白-1（LRP1）的水平同样降低。我们的数据表明，APOE4导致周细胞加速丢失，并增强周细胞和内皮细胞中LRP1依赖性CypA–MMP-9血脑屏障降解途径的激活，与AD APOE3携带者相比，这可介导AD APOE4中更大的血脑屏障损伤。
