apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain
apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain
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DOI：
10.1172/jci36663
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发表时间：
2008-12-01
影响因子：
15.9
通讯作者：
Zlokovic, Berislav V.
中科院分区：
文献类型：
--
作者：
Deane, Rashid;Sagare, Abhay;Zlokovic, Berislav V.
神经毒性淀粉样β肽（A β）在阿尔茨海默病（AD）患者的大脑中积累。APOE 4等位基因是散发性AD的主要危险因素，并与脑实质和血管淀粉样蛋白负荷增加相关。然而，apoE亚型如何影响A β在大脑中的积累仍不清楚。在这里，我们已经表明，apoE破坏A β清除小鼠血脑屏障（BBB）的亚型特异性的方式（特别是，apoE 4有一个更大的破坏作用比apoE 3或apoE 2）。与apoE 4结合的A β将游离A β 40/42从LDL受体相关蛋白1（LRP 1）快速清除到VLDL受体（VLDLR），后者在BBB内化apoE 4和A β-apoE 4复合物的速度比LRP 1慢。相反，apoE 2和apoE 3以及A β-apoE 2和A β-apoE 3复合物在BBB通过VLDLR和LRP 1以比A β-apoE 4复合物快得多的速率被清除。星形胶质细胞分泌的lipo-apoE 2、lipo-apoE 3和lipo-apoE 4以及它们与A β的复合物在血脑屏障被清除，其机制与它们各自的贫脂亚型相似，但速度慢2- 3倍。因此，apoE亚型差异调节A β从大脑中的清除，这可能有助于APOE基因型对AD患者和AD动物模型的疾病过程的影响。
Neurotoxic amyloid beta peptide (A beta) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence A beta accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts A beta clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). A beta binding to apoE4 redirected the rapid clearance of free A beta 40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and A beta-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as A beta-apoE2 and A beta-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than A beta-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with A beta were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate A beta clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.