Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

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.

ACKNOWLEDGMENTS

We thank C. Scott (Kolling Institute of Medical Research, NSW, Australia) for the anti-IGF-II receptor antibody. We also are grateful to Michelle Montgomery and Tsuneya Ikezu for assistance with the adenovirus work.

S.K., Y.W., and G.T. conceived and designed the experiments. Y.W., V.B.-P., and M.E.Z. performed the experiments. Y.W., V.B.-P., M.E.Z., R.G.M., G.T., and S.K. analyzed the data. S.K., R.G.M., R.C.B., and G.T. contributed reagents/materials/analysis tools. Y.W., S.K., G.T., and R.G.M. wrote the paper.

This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (203518) and Canadian Institutes of Health Research (MOP-84480) to S.K., R01AG019070 grant from National Institutes on Aging (G.T.) and CIHR (MOPC133518) to R.C.B., and National Cancer Institute grant CA91885 to R.M. Y.W. is a recipient of doctoral awards from the Alzheimer Society of Canada and a graduate studentship award from Alberta Innovates-Health Solutions. V.B.-P. is supported by the BrightFocus Foundation Alzheimer's disease research award. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10OD010649), and flow cytometry was performed at the University of Chicago Flow Cytometry Core Facility. M.Z. is a recipient of a Davies Fellowship from the University of Nebraska Medical Center.