Major Involvement of Low-Density Lipoprotein Receptor-Related Protein 1 in the Clearance of Plasma Free Amyloid β-Peptide by the Liver
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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DOI：
10.1007/s11095-006-0208-7
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发表时间：
2006-06
影响因子：
3.7
通讯作者：
Chihiro Tamaki;S. Ohtsuki;T. Iwatsubo;T. Hashimoto;Kaoru Yamada;Chiori Yabuki;T. Terasaki
中科院分区：
文献类型：
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作者：
Chihiro Tamaki;S. Ohtsuki;T. Iwatsubo;T. Hashimoto;Kaoru Yamada;Chiori Yabuki;T. Terasaki
目的鉴定肝脏摄取淀粉样β-肽（1-40）（Aβ（1-40））的分子，方法采用肝脏摄取指数法研究大鼠肝脏摄取[125 I]Aβ（1 - 40）的机制（50%饱和浓度= 302 nM）。Aβ片段的抑制谱表明，Aβ 17-24（LVFFAEDV）是负责肝Aβ（1-40）摄取的假定序列。受体相关蛋白（RAP）抑制[125 I]Aβ（1-40）摄取48%。RAP缺陷小鼠的低密度脂蛋白受体相关蛋白1（LRP-1）表达受到抑制，肝脏对[125 I]Aβ（1-40）的摄取减少了46%。siRNA介导的肝脏LRP-1表达抑制导致[125 I]Aβ（1-40）摄取减少64%。与7周龄大鼠相比，13月龄大鼠肝脏LRP-1的表达和肝脏Aβ（1-40）摄取均显著降低。结论LRP-1是肝脏饱和摄取血浆游离Aβ（1-40）的主要受体。LRP-1表达的降低将在年龄相关的肝脏Aβ（1-40）清除率降低中发挥作用。
PurposeTo 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).MethodsThe liver uptake index method was used to examine the mechanisms of Aβ(1–40) uptake by the liverin vivo.Results[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.ConclusionsLRP-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.