LDLR-related protein 10 trafficking and processing: evidence for a role in Alzheimer's disease

Background The A[beta] peptide that accumulates in Alzheimer's disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by [beta]- and [gamma]-secretases. Substantial evidence indicates that alterations in APP trafficking within the secretory and endocytic pathways dir...

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Bibliographic Details
Published in:	Molecular neurodegeneration Vol. 7
Main Authors:	Brodeur, Julie, Thñriault, Caroline, Lessard-Beaudoin, Mñlissa, Marcil, Alexandre, Dahan, Sophie, Lavoie, Christine
Format:	Journal Article
Language:	English
Published:	BioMed Central Ltd 26-06-2012
Subjects:	Advertising executives Alzheimer's disease Amyloid beta-protein Development and progression Low density lipoproteins Physiological aspects Proteolysis Canada
Online Access:	Get full text
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Summary:	Background The A[beta] peptide that accumulates in Alzheimer's disease (AD) is derived from amyloid precursor protein (APP) following proteolysis by [beta]- and [gamma]-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 A[beta] 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 A[beta] production. Results 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 A[beta], while knockdown of LRP10 expression increases A[beta] 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 [beta]-cleavage into A[beta]. Furthermore, expression of LRP10 is significantly lower in the post-mortem brain tissues of AD patients, supporting a possible role for LRP10 in AD. Conclusions 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. Keywords: LDLR-related protein 10 (LRP10), Amyloid precursor protein (APP), Amyloid beta (A[beta]), Intracellular trafficking, Alzheimer's disease, Endosome, Trans-Golgi network (TGN), Low density lipoprotein receptor (LDLR)
ISSN:	1750-1326 1750-1326
DOI:	10.1186/1750-1326-7-31