Cerebral clearance of human amyloid-beta 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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Authors: | Ito Shingo Ohtsuki Sumio Kamiie Junichi Nezu Yasuko Terasaki Tetsuya |
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Institution: | Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan; SORST of the Japan Science and Technology Agency, Japan |
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Abstract: | Soluble amyloid-β peptide (Aβ) exists in the form of monomers and oligomers, and as complexes with Aβ-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 Aβ(1–40) hAβ(1–40)] from the rat brain across the blood–brain barrier. Incubation of 125I]hAβ(1–40) monomer resulted in time-dependent and temperature-dependent dimer formation, and the apparent elimination rate of 125I]hAβ(1–40) dimer was significantly decreased by 92.7% compared with that of 125I]hAβ(1–40) monomer. Pre-incubation with LRP-1 ligands, such as activated α2-macroglobulin (α2M), apolipoprotein E2 (apoE2), apoE3, apoE4, and lactoferrin, reduced the elimination of 125I]hAβ(1–40). By contrast, pre-administration of the same concentration of these molecules in the rat brain did not significantly inhibit 125I]hAβ(1–40) monomer elimination. Purified 125I]hAβ(1–40)/activated α2M complex and 125I]activated α2M were not significantly eliminated from the rat brain up to 60 min. MEF-1 cells, which have LRP-1-mediated endocytosis, exhibited uptake of 125I]activated α2M, and enhancement of 125I]hAβ(1–40) uptake upon pre-incubation with apoE, suggesting that 125I]activated α2M and 125I]hAβ(1–40)/apoE complex function as LRP-1 ligands. These findings indicate that dimerization and LRP-1-ligand complex formation prevent the elimination of hAβ(1–40) from the brain across the blood–brain barrier. |
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Keywords: | Alzheimer's disease amyloid-β peptide apolipoprotein E blood–brain barrier low-density lipoprotein receptor-related protein-1 α2-macroglobulin |
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