Pharmaceutical Research

, Volume 23, Issue 7, pp 1407–1416

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
Featured Article

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.

Key Words

amyloid β-peptide clearance liver uptake index low-density lipoprotein receptor-related protein 1 receptor-mediated endocytosis 

Abbreviations

amyloid β-peptide

AD

Alzheimer's disease

AGEs

advanced glycation end products

apoE

apolipoprotein E

BBB

blood–brain barrier

BSA

bovine serum albumin

CAA

cerebrovascular amyloid angiopathy

FITC

fluorescein-4-isothiocyanate

LDL

low-density lipoprotein

LRP-1

LDL receptor-related protein 1

LUI

liver uptake index

RAGE

receptor for AGEs

RAP

receptor-associated protein

SDS

sodium dodecylsulfate

siRNA

short interfering RNA

SR-A

scavenger receptor type A

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Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Chihiro Tamaki
    • 1
  • Sumio Ohtsuki
    • 1
    • 2
    • 3
  • Takeshi Iwatsubo
    • 4
  • Tadafumi Hashimoto
    • 4
  • Kaoru Yamada
    • 4
  • Chiori Yabuki
    • 4
  • Tetsuya Terasaki
    • 1
    • 2
    • 3
  1. 1.Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical SciencesTohoku UniversityAoba-kuJapan
  2. 2.New Industry Creation Hatchery CenterTohoku UniversityAoba-kuJapan
  3. 3.SORST of Japan Science and Technology Agency (JST) Japan
  4. 4.Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical SciencesUniversity of TokyoBunkyokuJapan

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