Cerebral clearance of human amyloid-β peptide (1-40) across the blood-brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes
Cerebral clearance of human amyloid-β peptide (1-40) across the blood-brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes
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DOI：
10.1111/j.1471-4159.2007.04938.x
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发表时间：
2007-12-01
影响因子：
4.7
通讯作者：
Terasaki, Tetsuya
中科院分区：
文献类型：
--
作者：
Ito, Shingo;Ohtsuki, Sumio;Terasaki, Tetsuya
可溶性淀粉样β蛋白(Aβ)以单体和低聚物的形式存在，并与Aβ结合分子形成复合体，如低密度脂蛋白受体相关蛋白1(LRP-1)配体。本研究探讨了自聚集和LRP-1配体对跨越血脑屏障的大鼠脑内人Aβ(1-40)[HAβ(1-40)]清除的影响。[I-125]HAβ(1-40)单体与[I-125]HAβ(1-40)单体孵育可形成依赖于时间和温度的二聚体，与[I-125]HAβ(1-40)单体相比，[I-125]HAβ(1-40)二聚体的表观清除率显著降低92.7%。LRP-1配体，如激活的α2-巨球蛋白(α2M)、载脂蛋白E2(APOE2)、载脂蛋白E3、载脂蛋白E4和乳铁蛋白预先孵育，可减少[I-125]HAβ(1-40)的消除。相比之下，在大鼠大脑中预先给予相同浓度的这些分子并没有显著抑制[I-125]HAβ(1-40)单体的消除。纯化的[I-125]HAβ(1-40)/活化的α2M复合体和[I-125]活化的α2M在60min内仍未从大鼠脑中显著清除。具有LRP-1介导的内吞作用的MEF-1细胞摄取[I-125]激活的α2M，并在与apoE预先孵育后摄取[I-125]HAβ(1-40)，提示[I-125]激活的α2M和[I-125]HAβ(1-40)/apoE复合体作为LRP-1配体发挥作用。这些发现表明，二聚化和LRP-1-配体复合体的形成阻止了HAβ(1-40)通过血脑屏障从大脑中清除。
Soluble amyloid-beta peptide (A beta) exists in the form of monomers and oligomers, and as complexes with A beta-binding molecules, such as low-density lipoprotein receptor-related protein-1 (LRP-1) ligands. The present study investigated the effect of self-aggregation and LRP-1 ligands on the elimination of human A beta(1-40) [hA beta(1-40)] from the rat brain across the blood-brain barrier. Incubation of [I-125]hA beta(1-40) monomer resulted in time-dependent and temperature-dependent dimer formation, and the apparent elimination rate of [I-125]hA beta(1-40) dimer was significantly decreased by 92.7% compared with that of [I-125]hA beta(1-40) monomer. Pre-incubation with LRP-1 ligands, such as activated alpha 2-macroglobulin (alpha 2M), apolipoprotein E2 (apoE2), apoE3, apoE4, and lactoferrin, reduced the elimination of [I-125]hA beta(1-40). By contrast, pre-administration of the same concentration of these molecules in the rat brain did not significantly inhibit [I-125]hA beta(1-40) monomer elimination. Purified [I-125]hA beta(1-40)/activated alpha 2M complex and [I-125]activated alpha 2M were not significantly eliminated from the rat brain up to 60 min. MEF-1 cells, which have LRP-1-mediated endocytosis, exhibited uptake of [I-125]activated alpha 2M, and enhancement of [I-125]hA beta(1-40) uptake upon pre-incubation with apoE, suggesting that [I-125]activated alpha 2M and [I-125]hA beta(1-40)/apoE complex function as LRP-1 ligands. These findings indicate that dimerization and LRP-1-ligand complex formation prevent the elimination of hA beta(1-40) from the brain across the blood-brain barrier.