The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1.

von Einem B; Schwanzar D; Rehn F; Beyer AS; Weber P; Wagner M; Schneckenburger H; von Arnim CA

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The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1.

机译：低密度受体相关蛋白1（LRP1）作为BACE1的淀粉样前体蛋白（APP）的竞争底物的作用。

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Cleavage of APP by BACE1 is the first proteolytic step in the production of amyloid-beta (Abeta), which accumulates in senile plaques in Alzheimer's disease. Through its interaction with APP, the low-density receptor-related protein 1 (LRP1) enhances APP internalization. Recently, BACE1 has been shown to interact with and cleave the light chain (lc) of LRP1. Since LRP1 is known to compete with APP for cleavage by gamma-secretase, we tested the hypothesis that LRP1 also acts as a competitive substrate for beta-secretase. We found that the increase in secreted APP (sAPP) mediated by over-expression of BACE1 in APP-transfected cells could be decreased by simultaneous LRP1 over-expression. Analysis by multi-spot ELISA revealed that this is due to a decrease in sAPPbeta, but not sAPPalpha. Interaction between APP and BACE1, as measured by immunoprecipitation and fluorescence lifetime assays, was impaired by LRP1 over-expression. We also demonstrate that APP over-expression leads to decreased LRP1 association with and cleavage by BACE1. In conclusion, our data suggest that--in addition to its role in APP trafficking--LRP1 affects APP processing by competing for cleavage by BACE1.

机译：BACE1对APP的切割是淀粉样β（Abeta）产生的第一步蛋白水解步骤，该蛋白在阿尔茨海默氏病的老年斑中积累。通过与APP的相互作用，低密度受体相关蛋白1（LRP1）增强了APP的内在化。最近，已显示BACE1与LRP1的轻链（lc）相互作用并裂解。由于已知LRP1与APP竞争被γ-分泌酶裂解，因此我们检验了LRP1也是β-分泌酶竞争底物的假设。我们发现，由APP转染的细胞中BACE1的过表达介导的分泌APP（sAPP）的增加可通过同时LRP1的过表达而减少。通过多点ELISA的分析表明，这是由于sAPPbeta降低，而不是sAPPalpha降低。 LRP1过表达会削弱APP和BACE1之间的相互作用，如通过免疫沉淀和荧光寿命测定所测量的。我们还证明APP的过表达导致与BACE1的LRP1缔合和切割减少。总之，我们的数据表明，除了其在APP交易中的作用外，LRP1还通过竞争BACE1的切割作用影响APP的加工。

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《Experimental Neurology》 |2010年第1期|共9页
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von Einem B; Schwanzar D; Rehn F; Beyer AS; Weber P; Wagner M; Schneckenburger H; von Arnim CA;
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中图分类神经病学与精神病学;
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1. The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1. [J] . von Einem B, Schwanzar D, Rehn F, Experimental Neurology . 2010,第1期

机译：低密度受体相关蛋白1（LRP1）作为BACE1的淀粉样前体蛋白（APP）的竞争底物的作用。
2. Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce, or otherwise alter, amyloid deposition in APPswe/PS1dE9 transgenic mice [J] . Guilian Xu, Cameron C Green, Susan E Fromholt, Alzheimer s Research & Therapy . 2012,第2期

机译：海马神经元中低密度脂蛋白受体相关蛋白（LRP1）的减少不会成比例地减少或以其他方式改变APPswe / PS1dE9转基因小鼠的淀粉样蛋白沉积
3. Demonstration by fluorescence resonance energy transfer of two sites of interaction between the low-density lipoprotein receptor-related protein and the amyloid precursor protein: role of the intracellular adapter protein Fe65. [J] . Kinoshita A, Whelan CM, Smith CJ, The Journal of Neuroscience: The Official Journal of the Society for Neuroscience . 2001,第21期

机译：通过荧光共振能量转移证明低密度脂蛋白受体相关蛋白和淀粉样前体蛋白之间相互作用的两个位点：细胞内衔接子蛋白Fe65的作用。
4. Role of lysine residues in the interaction of blood coagulation factor VIII with its clearance receptor low-density lipoprotein receptor-related protein [C] . M. van den Biggelaar, J.H. Faber, M. Zuurveld, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2013

机译：赖氨酸残基在血液凝固因子VIII与其间隙受体低密度脂蛋白受体相关蛋白的作用
5. Opposing roles of the LDL receptor-related protein (LRP1) and the LDL receptor-related protein 1B (LRP1B) in beta-amyloid precursor protein (APP) trafficking and processing. [D] . Cam, Judith Ann. 2004

机译：LDL受体相关蛋白（LRP1）和LDL受体相关蛋白1B（LRP1B）在β-淀粉样前体蛋白（APP）的运输和加工中的作用相反。
6. Reduction of low-density lipoprotein receptor-related protein (LRP1) in hippocampal neurons does not proportionately reduce or otherwise alter amyloid deposition in APPswe/PS1dE9 transgenic mice [O] . Guilian Xu, Cameron C Green, Susan E Fromholt, 2012

机译：海马神经元中低密度脂蛋白受体相关蛋白（LRP1）的减少不会成比例地减少或以其他方式改变APPswe / PS1dE9转基因小鼠的淀粉样蛋白沉积
7. Low-Density Lipoprotein Receptor-Related Protein-1 (LRP1) C4408R Mutant Promotes Amyloid Precursor Protein (APP) α-Cleavage in Vitro [O] . Huayan Hou, Ahsan Habib, Dan Zi, 2017

机译：低密度脂蛋白受体相关蛋白-1（LRP1）C4408R突变体促进体外淀粉样蛋白前体蛋白（APP）α-切割

The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1.

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