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

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 [125I]hA[beta](1-40) monomer resulted in time-dependent and temperature-dependent dimer formation, and the apparent elimination rate of [125I]hA[beta](1-40) dimer was significantly decreased by 92.7% compared with that of [125I]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 [125I]hA[beta](1-40). By contrast, pre-administration of the same concentration of these molecules in the rat brain did not significantly inhibit [125I]hA[beta](1-40) monomer elimination. Purified [125I]hA[beta](1-40)/activated [alpha]2M complex and [125I]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 [125I]activated [alpha]2M, and enhancement of [125I]hA[beta](1-40) uptake upon pre-incubation with apoE, suggesting that [125I]activated [alpha]2M and [125I]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. [PUBLICATION ABSTRACT]