The Low Density Lipoprotein Receptor-related Protein 1 Mediates Uptake of Amyloid β Peptides in an in Vitro Model of the Blood-Brain Barrier Cells

• Published in: The Journal of biological chemistry 2008-12, Vol.283 (50), p.34554-34562
• Main Authors: Yamada, Kaoru, Hashimoto, Tadafumi, Yabuki, Chiori, Nagae, Yusuke, Tachikawa, Masanori, Strickland, Dudley K., Liu, Qiang, Bu, Guojun, Basak, Jacob M., Holtzman, David M., Ohtsuki, Sumio, Terasaki, Tetsuya, Iwatsubo, Takeshi
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - pharmacokinetics; Animals; Blood-Brain Barrier; Brain - metabolism; Cell Line, Tumor; Collagen - metabolism; Fibroblasts - metabolism; Gene Expression Regulation; Humans; In Vitro Techniques; Low Density Lipoprotein Receptor-Related Protein-1 - physiology; Mice; Models, Biological; Protein Transport; Rats; Receptors, LDL - physiology; Tumor Suppressor Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M801487200

The metabolism of amyloid β peptide (Aβ) in the brain is crucial to the pathogenesis of Alzheimer disease. A body of evidence suggests that Aβ is actively transported from brain parenchyma to blood across the blood-brain barrier (BBB), although the precise mechanism remains unclear. To unravel the cellular and molecular mechanism of Aβ transport across the BBB, we established a new in vitro model of the initial internalization step of Aβ transport using TR-BBB cells, a conditionally immortalized endothelial cell line from rat brain. We show that TR-BBB cells rapidly internalize Aβ through a receptor-mediated mechanism. We also provide evidence that Aβ internalization is mediated by LRP1 (low density lipoprotein receptor-related protein 1), since administration of LRP1 antagonist, receptor-associated protein, neutralizing antibody, or small interference RNAs all reduced Aβ uptake. Despite the requirement of LRP1-dependent internalization, Aβ does not directly bind to LRP1 in an in vitro binding assay. Unlike TR-BBB cells, mouse embryonic fibroblasts endogenously expressing functional LRP1 and exhibiting the authentic LRP1-mediated endocytosis (e.g. of tissue plasminogen activator) did not show rapid Aβ uptake. Based on these data, we propose that the rapid LRP1-dependent internalization of Aβ occurs under the BBB-specific cellular context and that TR-BBB is a useful tool for analyzing the molecular mechanism of the rapid transport of Aβ across BBB.