Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid β-peptide by the liver

Chihiro Tamaki, Sumio Ohtsuki, Takeshi Iwatsubo, Tadafumi Hashimoto, Kaoru Yamada, Chiori Yabuki, Tetsuya Terasaki

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68 Citations (Scopus)

Abstract

Purpose. To identify the molecules responsible for amyloid β-peptide (1-40) (Aβ(1-40)) uptake by the liver, which play a major role in the systemic clearance of Aβ(1-40). Methods. The liver uptake index method was used to examine the mechanisms of Aβ(1-40) uptake by the liver in vivo. Results. [125I]Aβ(1-40) uptake by the rat liver was concentration-dependent (50% saturation concentration = 302 nM). The inhibitory spectrum of Aβ fragments indicated that 17-24 in Aβ (LVFFAEDV) was the putative sequence responsible for hepatic Aβ(1-40) uptake. Receptor-associated protein (RAP) inhibited [125I]Aβ(1-40) uptake by 48%. RAP-deficient mice, in which low-density lipoprotein receptor-related protein 1 (LRP-1) expression was suppressed, showed a 46% reduction in [125I]Aβ(1-40) uptake by the liver. siRNA-mediated suppression of LRP-1 expression in the liver resulted in a reduction in [ 125I]Aβ(1-40) uptake by 64%. Both the expression of LRP-1 in the liver and the hepatic Aβ(1-40) uptake were significantly reduced in 13-month-old rats compared with 7-week-old rats. Conclusions. LRP-1 is the major receptor responsible for the saturable uptake of plasma free Aβ(1-40) by the liver. Reduction of LRP-1 expression will play a role in the age-related reduction in hepatic Aβ(1-40) clearance.

Original languageEnglish
Pages (from-to)1407-1416
Number of pages10
JournalPharmaceutical research
Volume23
Issue number7
DOIs
Publication statusPublished - 2006 Jul 1

Keywords

  • Amyloid β-peptide
  • Clearance
  • Liver uptake index
  • Low-density lipoprotein receptor-related protein 1
  • Receptor-mediated endocytosis

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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