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

Purpose. To identify the molecules responsible for amyloid beta-peptide (1-40) (A beta(1-40)) uptake by the liver, which play a major role in the systemic clearance of A beta(1-40). Methods. The liver uptake index method was used to examine the mechanisms of A beta(1-40) uptake by the liver in vivo. Results. [I-125]A beta(1-40) uptake by the rat liver was concentration-dependent (50% saturation concentration = 302 nM). The inhibitory spectrum of A beta fragments indicated that 17-24 in A beta (LVFFAEDV) was the putative sequence responsible for hepatic A beta(1-40) uptake. Receptor-associated protein (RAP) inhibited [I-125]A beta(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 [I-125]A beta(1-40) uptake by the liver. siRNA-mediated suppression of LRP-1 expression in the liver resulted in a reduction in [I-125]A beta(1-40) uptake by 64%. Both the expression of LRP-1 in the liver and the hepatic A beta(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 A beta(1-40) by the liver. Reduction of LRP-1 expression will play a role in the age-related reduction in hepatic A beta(1-40) clearance.