Involvement of insulin-like growth factor 1 receptor signaling in the amyloid-β peptide oligomers-induced p75 neurotrophin receptor protein expression in mouse hippocampus

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DOIResolve DOI: http://doi.org/10.3233/JAD-2012-120046
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TypeArticle
Journal titleJournal of Alzheimer's Disease
ISSN1387-2877
Volume31
Issue3
Pages493506; # of pages: 14
Subjectamyloid beta protein[1-42]; neurotrophin receptor p75; oligomer; somatomedin C receptor; Alzheimer disease; animal experiment; animal model; animal tissue; article; controlled study; disease model; female; hippocampus; human; human cell; in vivo study; male; microinjection; mouse; neuroblastoma cell; nonhuman; priority journal; protein expression; protein phosphorylation; transgenic mouse; wild type; Amyloid beta-Peptides; Animals; Cell Line, Tumor; Female; Gene Expression Regulation; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments; Receptor, IGF Type 1; Receptors, Nerve Growth Factor; Signal Transduction
AbstractThe p75 neurotrophin receptor (p75NTR) has been thought to play a critical role in amyloid-β peptide (Aβ)-mediated neurodegeneration and Aβ metabolism in Alzheimer's disease (AD) brains. Our previous report showed that membrane-associated p75NTR protein expression was significantly increased in the hippocampi of two different strains of transgenic AD mice and was associated with the age-dependent elevation of Aβ1-42 levels. Here, we provide evidence that the Aβ1-42 oligomers known as ADDLs (Aβ-derived diffusible ligands) induce p75NTR protein expression through insulin-like growth factor 1 receptor (IGF-1R) phosphorylation in SH-SY5Y human neuroblastoma cells. An in vivo microinjection study demonstrated that microinjected ADDLs increased the p75NTR protein expression by 1.4-fold in the ipsilateral hippocampus compared to the contralateral hippocampus. In addition, ADDLs microinjected into mouse hippocampi facilitated IGF-1R phosphorylation within 30 min and the co-administration of picropodophyllin, an IGF-1R kinase inhibitor, blocked ADDLs-induced p75NTR expression. We examined the possible involvement of IGF-1R in the increased p75NTR protein expression in the hippocampi of 6-month-old AβPPswe/PS1dE9 AD model mice that had accumulated significant amounts of Aβ1-42 and showed significantly higher p75NTR expression than age-matched wild-type mice. We found that IGF-1R phosphorylation in these transgenic mice was higher than that in the wild-type mice. These findings indicate that Aβ1-42 oligomers stimulate the p75NTR protein expression in the hippocampus through IGF-1R signaling. Thus, Aβ1-42 oligomers-mediated IGF-1R activation may trigger an increase in p75NTR protein expression in the hippocampus of AD brain during the early stages of disease development. © 2012-IOS Press and the authors. All rights reserved.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); NRC Institute for Biological Sciences (IBS-ISB)
Peer reviewedYes
NPARC number21269274
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Record identifierb39b0d6c-9fc8-4279-ae5d-e20c207c68c4
Record created2013-12-12
Record modified2016-05-09
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