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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.
J Neurochem. 2007 Dec; 103(6):2482-90.JN

Abstract

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17908238

Citation

Ito, Shingo, et al. "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." Journal of Neurochemistry, vol. 103, no. 6, 2007, pp. 2482-90.
Ito S, Ohtsuki S, Kamiie J, et al. 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. J Neurochem. 2007;103(6):2482-90.
Ito, S., Ohtsuki, S., Kamiie, J., Nezu, Y., & Terasaki, T. (2007). 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. Journal of Neurochemistry, 103(6), 2482-90.
Ito S, et al. 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. J Neurochem. 2007;103(6):2482-90. PubMed PMID: 17908238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ito,Shingo, AU - Ohtsuki,Sumio, AU - Kamiie,Junichi, AU - Nezu,Yasuko, AU - Terasaki,Tetsuya, Y1 - 2007/10/01/ PY - 2007/10/3/pubmed PY - 2008/1/9/medline PY - 2007/10/3/entrez SP - 2482 EP - 90 JF - Journal of neurochemistry JO - J Neurochem VL - 103 IS - 6 N2 - 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. SN - 1471-4159 UR - https://www.unboundmedicine.com/medline/citation/17908238/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_ L2 - https://doi.org/10.1111/j.1471-4159.2007.04938.x DB - PRIME DP - Unbound Medicine ER -