Major involvement of low-density lipoprotein receptor-related protein 1 in the clearance of plasma free amyloid beta-peptide by the liver.
OBJECTIVE
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.
Tamaki
Chihiro
C
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan.
Ohtsuki
Sumio
S
Iwatsubo
Takeshi
T
Hashimoto
Tadafumi
T
Yamada
Kaoru
K
Yabuki
Chiori
C
Terasaki
Tetsuya
T
D000367:Age Factors; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016650:Fluorescein-5-isothiocyanate; D022781:Hepatocytes / Q000378:metabolism; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D026563:LDL-Receptor Related Protein-Associated Protein / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes; D026563:LDL-Receptor Related Protein-Associated Protein; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010446:Peptide Fragments; C084358:amyloid beta-protein (1-28); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C092395:amyloid beta-protein (12-28); D016650:Fluorescein-5-isothiocyanate