TY - JOUR
T1 - 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
AU - Ito, Shingo
AU - Ohtsuki, Sumio
AU - Kamiie, Junichi
AU - Nezu, Yasuko
AU - Terasaki, Tetsuya
PY - 2007/12/1
Y1 - 2007/12/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Amyloid-β peptide
KW - Apolipoprotein E
KW - Blood-brain barrier
KW - Low-density lipoprotein receptor-related protein-1
KW - α2- macroglobulin
UR - http://www.scopus.com/inward/record.url?scp=36448976927&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=36448976927&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2007.04938.x
DO - 10.1111/j.1471-4159.2007.04938.x
M3 - Article
C2 - 17908238
AN - SCOPUS:36448976927
VL - 103
SP - 2482
EP - 2490
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -