Tamaki Chihiro, Ohtsuki Sumio, Iwatsubo Takeshi, Hashimoto Tadafumi, Yamada Kaoru, Yabuki Chiori, Terasaki Tetsuya
Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan.
Pharm Res. 2006 Jul;23(7):1407-16. doi: 10.1007/s11095-006-0208-7. Epub 2006 Jun 21.
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).
The liver uptake index method was used to examine the mechanisms of Abeta(1-40) uptake by the liver in vivo.
[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.
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.
鉴定肝脏摄取β淀粉样肽（1-40）（Aβ（1-40））的相关分子，这些分子在Aβ（1-40）的全身清除中起主要作用。
采用肝脏摄取指数法在体内研究肝脏摄取Aβ（1-40）的机制。
大鼠肝脏对[125I]Aβ（1-40）的摄取呈浓度依赖性（50%饱和浓度=302 nM）。Aβ片段的抑制谱表明，Aβ中的17-24位（LVFFAEDV）是肝脏摄取Aβ（1-40）的假定序列。受体相关蛋白（RAP）抑制[125I]Aβ（1-40）摄取达48%。低密度脂蛋白受体相关蛋白1（LRP-1）表达受抑制的RAP缺陷小鼠，肝脏对[125I]Aβ（1-40）的摄取降低了46%。小干扰RNA介导的肝脏中LRP-1表达的抑制导致[125I]Aβ（1-40）摄取降低64%。与7周龄大鼠相比，13月龄大鼠肝脏中LRP-1的表达及肝脏对Aβ（1-40）的摄取均显著降低。
LRP-1是肝脏对血浆游离Aβ（1-40）进行可饱和摄取的主要受体。LRP-1表达的降低在与年龄相关的肝脏Aβ（1-40）清除减少中起作用。
