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 (Abeta) exists in the form of monomers and oligomers, and as complexes with Abeta-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 Abeta(1-40) [hAbeta(1-40)] from the rat brain across the blood-brain barrier. Incubation of [(125)I]hAbeta(1-40) monomer resulted in time-dependent and temperature-dependent dimer formation, and the apparent elimination rate of [(125)I]hAbeta(1-40) dimer was significantly decreased by 92.7% compared with that of [(125)I]hAbeta(1-40) monomer. Pre-incubation with LRP-1 ligands, such as activated alpha2-macroglobulin (alpha2M), apolipoprotein E2 (apoE2), apoE3, apoE4, and lactoferrin, reduced the elimination of [(125)I]hAbeta(1-40). By contrast, pre-administration of the same concentration of these molecules in the rat brain did not significantly inhibit [(125)I]hAbeta(1-40) monomer elimination. Purified [(125)I]hAbeta(1-40)/activated alpha2M complex and [(125)I]activated alpha2M were not significantly eliminated from the rat brain up to 60 min. MEF-1 cells, which have LRP-1-mediated endocytosis, exhibited uptake of [(125)I]activated alpha2M, and enhancement of [(125)I]hAbeta(1-40) uptake upon pre-incubation with apoE, suggesting that [(125)I]activated alpha2M and [(125)I]hAbeta(1-40)/apoE complex function as LRP-1 ligands. These findings indicate that dimerization and LRP-1-ligand complex formation prevent the elimination of hAbeta(1-40) from the brain across the blood-brain barrier.
Ito
Shingo
S
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan, and SORST of the Japan Science and Technology Agency, Japan.
Ohtsuki
Sumio
S
Kamiie
Junichi
J
Nezu
Yasuko
Y
Terasaki
Tetsuya
T
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D019281:Dimerization; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000187:drug effects / Q000378:metabolism*; D046911:Macromolecular Substances / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D046911:Macromolecular Substances; D010446:Peptide Fragments; D000511:alpha-Macroglobulins; C078592:amyloid beta-protein (1-40); D007781:Lactoferrin