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Major Involvement of Low-Density Lipoprotein Receptor-Related Protein 1 in the Clearance of Plasma Free Amyloid β-Peptide by the Liver

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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.

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Abbreviations

Aβ:

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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Acknowledgments

We would like to thank Dr. T. Yokota for valuable discussions, and Ms. N. Funayama for secretarial assistance. This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas 17025005 from The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and a 21st Century Center of Excellence (COE) Program grant from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan

    Chihiro Tamaki, Sumio Ohtsuki & Tetsuya Terasaki

  2. New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan

    Sumio Ohtsuki & Tetsuya Terasaki

  3. SORST of Japan Science and Technology Agency (JST),  , Japan

    Sumio Ohtsuki & Tetsuya Terasaki

  4. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo, 113-0033, Japan

    Takeshi Iwatsubo, Tadafumi Hashimoto, Kaoru Yamada & Chiori Yabuki

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  1. Chihiro Tamaki
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Tamaki, C., Ohtsuki, S., Iwatsubo, T. et al. Major Involvement of Low-Density Lipoprotein Receptor-Related Protein 1 in the Clearance of Plasma Free Amyloid β-Peptide by the Liver. Pharm Res 23, 1407–1416 (2006). https://doi.org/10.1007/s11095-006-0208-7

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