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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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. © 2007 The Authors.

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APA

Ito, S., Ohtsuki, S., Kamiie, J., Nezu, Y., & Terasaki, T. (2007). 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. Journal of Neurochemistry, 103(6), 2482–2490. https://doi.org/10.1111/j.1471-4159.2007.04938.x

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