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

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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