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Comparative Study
. 2006 Jul;23(7):1407-16.
doi: 10.1007/s11095-006-0208-7. Epub 2006 Jun 21.

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

Chihiro Tamaki  1 , Sumio Ohtsuki, Takeshi Iwatsubo, Tadafumi Hashimoto, Kaoru Yamada, Chiori Yabuki, Tetsuya Terasaki
Affiliations
Comparative Study

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

Chihiro Tamaki et al. Pharm Res. 2006 Jul.

Abstract

Purpose: To identify the molecules responsible for amyloid beta-peptide (1-40) (Abeta(1-40)) uptake by the liver, which play a major role in the systemic clearance of Abeta(1-40).

Methods: The liver uptake index method was used to examine the mechanisms of Abeta(1-40) uptake by the liver in vivo.

Results: [125I]Abeta(1-40) uptake by the rat liver was concentration-dependent (50% saturation concentration = 302 nM). The inhibitory spectrum of Abeta fragments indicated that 17-24 in Abeta (LVFFAEDV) was the putative sequence responsible for hepatic Abeta(1-40) uptake. Receptor-associated protein (RAP) inhibited [125I]Abeta(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]Abeta(1-40) uptake by the liver. siRNA-mediated suppression of LRP-1 expression in the liver resulted in a reduction in [125I]Abeta(1-40) uptake by 64%. Both the expression of LRP-1 in the liver and the hepatic Abeta(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 Abeta(1-40) by the liver. Reduction of LRP-1 expression will play a role in the age-related reduction in hepatic Abeta(1-40) clearance.

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