LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease.
LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer's disease.
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LDLR相关的蛋白10（LRP10）调节淀粉样蛋白前体蛋白（APP）运输和加工：在阿尔茨海默氏病中作用的证据。
DOI：
10.1186/1750-1326-7-31
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发表时间：
2012-06-26
影响因子：
15.1
通讯作者：
Lavoie C
中科院分区：
文献类型：
--
作者：
Brodeur J;Thériault C;Lessard-Beaudoin M;Marcil A;Dahan S;Lavoie C
在阿尔茨海默病（AD）中积累的Aβ肽来源于淀粉样前体蛋白（APP），随后由β-和γ-分泌酶进行蛋白水解。大量证据表明，分泌和内吞途径中APP运输的改变直接影响APP与这些分泌酶的相互作用以及随后的Aβ产生。据报道，低密度脂蛋白受体（LDLR）家族的各种成员在APP运输和加工中发挥作用，是AD的重要危险因素。我们最近表征了LDLR家族的一个独特成员，称为LDLR相关蛋白10（LRP 10），其在trans-Golgi网络（TGN），质膜（PM）和内体之间穿梭。我们研究了LRP 10是否参与APP的胞内运输和Aβ的产生。在这份报告中，我们提供的证据表明，LRP 10是一个功能性APP受体参与APP贩运和加工。LRP 10直接与APP的胞外域相互作用，并与APP共定位于TGN。LRP 10在人神经母细胞瘤SH-SY 5 Y细胞中的表达增加诱导成熟APP在高尔基体中的积累，并减少其在细胞表面的存在及其加工成Aβ，而LRP 10表达的敲低增加Aβ的产生。负责LRP 10再循环至TGN的关键基序的突变导致APP与LRP 10异常重新分布至早期内体，并伴随APP β裂解为Aβ的增加。此外，LRP 10的表达在AD患者的死后脑组织中显著较低，支持LRP 10在AD中的可能作用。本研究确定LRP 10是一种新型APP分选受体，可保护APP免受淀粉样蛋白加工，这表明LRP 10功能的降低可能有助于阿尔茨海默病的发病机制。
The Aβ peptide that accumulates in Alzheimer’s disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by β- and γ-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways directly impact the interaction of APP with these secretases and subsequent Aβ production. Various members of the low-density lipoprotein receptor (LDLR) family have been reported to play a role in APP trafficking and processing and are important risk factors in AD. We recently characterized a distinct member of the LDLR family called LDLR-related protein 10 (LRP10) that shuttles between the trans-Golgi Network (TGN), plasma membrane (PM), and endosomes. Here we investigated whether LRP10 participates in APP intracellular trafficking and Aβ production. In this report, we provide evidence that LRP10 is a functional APP receptor involved in APP trafficking and processing. LRP10 interacts directly with the ectodomain of APP and colocalizes with APP at the TGN. Increased expression of LRP10 in human neuroblastoma SH-SY5Y cells induces the accumulation of mature APP in the Golgi and reduces its presence at the cell surface and its processing into Aβ, while knockdown of LRP10 expression increases Aβ production. Mutations of key motifs responsible for the recycling of LRP10 to the TGN results in the aberrant redistribution of APP with LRP10 to early endosomes and a concomitant increase in APP β-cleavage into Aβ. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD. The present study identified LRP10 as a novel APP sorting receptor that protects APP from amyloidogenic processing, suggesting that a decrease in LRP10 function may contribute to the pathogenesis of Alzheimer’s disease.