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
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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 [125 I]hAβ(1–40) monomer resulted in time‐dependent and temperature‐dependent dimer formation, and the apparent elimination rate of [125 I]hAβ(1–40) dimer was significantly decreased by 92.7% compared with that of [125 I]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 [125 I]hAβ(1–40). By contrast, pre‐administration of the same concentration of these molecules in the rat brain did not significantly inhibit [125 I]hAβ(1–40) monomer elimination. Purified [125 I]hAβ(1–40)/activated α2M complex and [125 I]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 [125 I]activated α2M, and enhancement of [125 I]hAβ(1–40) uptake upon pre‐incubation with apoE, suggesting that [125 I]activated α2M and [125 I]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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Accumulating recent evidence strongly suggests that when human apoE is complexed with Aβ, the brain to blood clearance of Aβ is actually decreased compared to that of free Aβ.
“Accumulating recent evidence strongly suggests that when human apoE is complexed with Aβ, the brain to blood clearance of Aβ is actually decreased compared to that of free Aβ (Bell et al., 2007; Deane et al., 2008; Ito et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Ito et al., 2007
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- Ab clearance reduction by complex formation 2489 Ó 2007 The Authors Journal Compilation Ó 2007 International Society for Neurochemistry, J. Neurochem. (2007) 103, 2482-2490 14714159, 2007, 6, · DOI
- S. Ito et al. Journal Compilation Ó 2007 International Society for Neurochemistry, J. Neurochem. (2007) 103, 2482-2490
- Ó 2007 The Authors 14714159, 2007, 6, · DOI
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- Authors
- Ito, S., Ohtsuki, S., Kamiie, J., Nezu, Y., & Terasaki, T.
- Affiliations
- Tohoku University (JP)
- Corresponding author
- Terasaki, Tetsuya
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2007-08-30
- Volume
- 103
- Issue
- 6
- Pages
- 2482-2490
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2064025889
- Cited by
- 85
- References
- 5
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 1 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 2 · 2013: 6 · 2012: 10
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Aβ(1-40), self-aggregation, dimerization, LRP1, alpha2-macroglobulin, apolipoprotein E, lactoferrin, endocytosis, amyloid-beta oligomers, Alzheimer's disease
- MeSH terms
- alpha-Macroglobulins, Alzheimer Disease, Animals, Apolipoproteins E, Blood-Brain Barrier, Cell Line, Cerebral Cortex, Endocytosis, Humans, Lactoferrin, Ligands, Male, Metabolic Clearance Rate, Peptide Fragments, Protein Binding, Amyloid beta-Peptides, Rats, Sprague-Dawley, Dimerization, Low Density Lipoprotein Receptor-Related Protein-1, Macromolecular Substances, Mice, Rats
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