Papers

Peer-reviewed
Jan, 2015

ApoE-isoform-dependent cellular uptake of amyloid-beta is mediated by lipoprotein receptor LR11/SorLA

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
  • Ryuji Yajima
  • ,
  • Takayoshi Tokutake
  • ,
  • Akihide Koyama
  • ,
  • Kensaku Kasuga
  • ,
  • Toshiyuki Tezuka
  • ,
  • Masatoyo Nishizawa
  • ,
  • Takeshi Ikeuchi

Volume
456
Number
1
First page
482
Last page
488
Language
English
Publishing type
Research paper (scientific journal)
DOI
10.1016/j.bbrc.2014.11.111
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE

The formation of senile plaques composed of beta-amyloid (A beta) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE epsilon 4 allele, the strong genetic factor for AD, facilitates the A beta deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-beta (A beta) through the binding of A beta to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of A beta through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4 > apoE3 > apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled A beta were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular A beta into the recipient cells was most prominently accentuated when co-cultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of A beta mediated by LR11/SorLA. (C) 2014 Elsevier Inc. All rights reserved.

Link information
DOI
https://doi.org/10.1016/j.bbrc.2014.11.111
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000348483600076&DestApp=WOS_CPL
ID information
  • DOI : 10.1016/j.bbrc.2014.11.111
  • ISSN : 0006-291X
  • eISSN : 1090-2104
  • Web of Science ID : WOS:000348483600076

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