Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability.
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.
Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
Y
Y
Wang
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, Illinois, USA.
V
V
Buggia-Prévot
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
M E
ME
Zavorka
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
R C
RC
Bleackley
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
R G
RG
MacDonald
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, Illinois, USA.
G
G
Thinakaran
Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada Department of Medicine, University of Alberta, Edmonton, Alberta, Canada skar@ualberta.ca.
S
S
Kar
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D017527:Receptor, IGF Type 2; D053829:Amyloid Precursor Protein Secretases; D019311:Staurosporine