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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- Tamaki, C., Ohtsuki, S., Iwatsubo, T. et al. Pharm Res (2006) 23: 1407. doi:10.1007/s11095-006-0208-7
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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).
The liver uptake index method was used to examine the mechanisms of Aβ(1–40) uptake by the liver in vivo.
[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.
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 Wordsamyloid β-peptide clearance liver uptake index low-density lipoprotein receptor-related protein 1 receptor-mediated endocytosis
advanced glycation end products
bovine serum albumin
cerebrovascular amyloid angiopathy
LDL receptor-related protein 1
liver uptake index
receptor for AGEs
short interfering RNA
scavenger receptor type A