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

Kaoru Yamada, Tadafumi Hashimoto, Chiori Yabuki, Yusuke Nagae, Masanori Tachikawa, Dudley K. Strickland, Qiang Liu, Guojun D Bu, Jacob M. Basak, David M. Holtzman, Sumio Ohtsuki, Tetsuya Terasaki, Takeshi Iwatsubo

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)34554-34562
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number50
DOIs
StatePublished - Dec 12 2008
Externally publishedYes

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Low Density Lipoprotein Receptor-Related Protein-1
Blood-Brain Barrier
Amyloid
Peptides
Brain
In Vitro Techniques
Endothelial cells
Tissue Plasminogen Activator
Fibroblasts
RNA Interference
Endocytosis
Neutralizing Antibodies
Metabolism
Rats
Assays
Alzheimer Disease
Blood
Endothelial Cells
RNA
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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. / Yamada, Kaoru; Hashimoto, Tadafumi; Yabuki, Chiori; Nagae, Yusuke; Tachikawa, Masanori; Strickland, Dudley K.; Liu, Qiang; Bu, Guojun D; Basak, Jacob M.; Holtzman, David M.; Ohtsuki, Sumio; Terasaki, Tetsuya; Iwatsubo, Takeshi.

In: Journal of Biological Chemistry, Vol. 283, No. 50, 12.12.2008, p. 34554-34562.

Research output: Contribution to journalArticle

Yamada, K, Hashimoto, T, Yabuki, C, Nagae, Y, Tachikawa, M, Strickland, DK, Liu, Q, Bu, GD, Basak, JM, Holtzman, DM, Ohtsuki, S, Terasaki, T & Iwatsubo, T 2008, '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', Journal of Biological Chemistry, vol. 283, no. 50, pp. 34554-34562. https://doi.org/10.1074/jbc.M801487200
Yamada, Kaoru ; Hashimoto, Tadafumi ; Yabuki, Chiori ; Nagae, Yusuke ; Tachikawa, Masanori ; Strickland, Dudley K. ; Liu, Qiang ; Bu, Guojun D ; Basak, Jacob M. ; Holtzman, David M. ; Ohtsuki, Sumio ; Terasaki, Tetsuya ; Iwatsubo, Takeshi. / 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. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 50. pp. 34554-34562.
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AU - Strickland, Dudley K.

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AU - Holtzman, David M.

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