Overexpression of the insulin-like growth factor II receptor increases β-amyloid production and affects cell viability

Y. Wang, V. Buggia-Prévot, M. E. Zavorka, R. C. Bleackley, Richard G MacDonald, G. Thinakaran, S. Kar

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Amyloid β (Aβ) peptides originating from amyloid precursor protein (APP) in the endosomal-lysosomal compartments play a critical role in the development of Alzheimer's disease (AD), the most common type of senile dementia affecting the elderly. Since insulin-like growth factor II (IGF-II) receptors facilitate the delivery of nascent lysosomal enzymes from the trans-Golgi network to endosomes, we evaluated their role in APP metabolism and cell viability using mouse fibroblast MS cells deficient in the murine IGF-II receptor and corresponding MS9II cells overexpressing the human IGF-II receptors. Our results show that IGF-II receptor overexpression increases the protein levels of APP. This is accompanied by an increase of β-site APP-cleaving enzyme 1 levels and an increase of β- and γ-secretase enzyme activities, leading to enhanced Aβ production. At the cellular level, IGF-II receptor overexpression causes localization of APP in perinuclear tubular structures, an increase of lipid raft components, and increased lipid raft partitioning of APP. Finally, MS9II cells are more susceptible to staurosporine-induced cytotoxicity, which can be attenuated by β-secretase inhibitor. Together, these results highlight the potential contribution of IGF-II receptor to AD pathology not only by regulating expression/processing of APP but also by its role in cellular vulnerability.

Original languageEnglish (US)
Pages (from-to)2368-2384
Number of pages17
JournalMolecular and cellular biology
Volume35
Issue number14
DOIs
StatePublished - Jan 1 2015

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IGF Type 2 Receptor
Amyloid beta-Protein Precursor
Amyloid
Cell Survival
Amyloid Precursor Protein Secretases
Alzheimer Disease
Enzymes
trans-Golgi Network
Lipids
Staurosporine
Endosomes
Fibroblasts
Pathology
Peptides

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Overexpression of the insulin-like growth factor II receptor increases β-amyloid production and affects cell viability. / Wang, Y.; Buggia-Prévot, V.; Zavorka, M. E.; Bleackley, R. C.; MacDonald, Richard G; Thinakaran, G.; Kar, S.

In: Molecular and cellular biology, Vol. 35, No. 14, 01.01.2015, p. 2368-2384.

Research output: Contribution to journalArticle

Wang, Y. ; Buggia-Prévot, V. ; Zavorka, M. E. ; Bleackley, R. C. ; MacDonald, Richard G ; Thinakaran, G. ; Kar, S. / Overexpression of the insulin-like growth factor II receptor increases β-amyloid production and affects cell viability. In: Molecular and cellular biology. 2015 ; Vol. 35, No. 14. pp. 2368-2384.
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