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

Shingo Ito, Sumio Ohtsuki, Junichi Kamiie, Yasuko Nezu, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2482-2490
Number of pages9
JournalJournal of Neurochemistry
Volume103
Issue number6
DOIs
Publication statusPublished - 2007 Dec 1

Keywords

  • Alzheimer's disease
  • Amyloid-β peptide
  • Apolipoprotein E
  • Blood-brain barrier
  • Low-density lipoprotein receptor-related protein-1
  • α2- macroglobulin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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