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Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer’s disease

Susanna Freude^*,,,1, Moritz M. Hettich^*,,,1, Christina Schumann^*,, Oliver Stöhr^*,,, Linda Koch^,,, Christoph Köhler^||, Michael Udelhoven^*,,, Uschi Leeser^*,,, Marita Müller^*,,, Naoto Kubota^¶, Takashi Kadowaki^¶, Wilhelm Krone^*,,, Hannsjörg Schröder^||, Jens C. Brüning^*,,,,# and Markus Schubert^*,,,2

^* Department of Internal Medicine II,

Center for Molecular Medicine Cologne (CMMC),

Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD),

Department of Mouse Genetics and Metabolism, Institute for Genetics, and

^|| Department II of Anatomy, University of Cologne, Cologne, Germany;

^¶ Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and

^# Max Planck Institute for the Biology of Ageing, Cologne, Germany

² Correspondence: Department of Internal Medicine II, University of Cologne, Kerpener Str. 62, LFI 4/061, 50937 Cologne, Germany. E-mail: markus.schubert{at}uni-koeln.de

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration leading to loss of cognitive abilities and ultimately to death. Postmortem investigations revealed decreased expression of cerebral insulin-like growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor substrate (IRS) proteins in patients with AD. To elucidate the role of insulin/IGF-1 signaling in AD, we crossed mice expressing the Swedish mutation of amyloid precursor protein (APP^SW, Tg2576 mice) as a model for AD with mice deficient for either IRS-2, neuronal IGF-1R (nIGF-1R^–/–), or neuronal insulin receptor (nIR^–/–), and analyzed survival, glucose, and APP metabolism. In the present study, we show that IRS-2 deficiency in Tg2576 mice completely reverses premature mortality in Tg2576 females and delays β-amyloid (Aβ) accumulation. Analysis of APP metabolism suggested that delayed Aβ accumulation resulted from decreased APP processing. To delineate the upstream signal responsible for IRS-2-mediated disease protection, we analyzed mice with nIGF-1R or nIR deficiency predominantly in the hippocampus. Interestingly, both male and female nIGF-1R^–/–Tg2576 mice were protected from premature death in the presence of decreased Aβ accumulation specifically in the hippocampus formation. However, neuronal IR deletion had no influence on lethality of Tg2576 mice. Thus, impaired IGF-1/IRS-2 signaling prevents premature death and delays amyloid accumulation in a model of AD.—Freude, S., Hettich, M. M., Schumann, C., Stöhr, O., Koch, L., Köhler, C., Udelhoven, M., Leeser, U., Müller, M., Kubota, N., Kadowaki, T., Krone, W., Schröder, H., Brüning, J. C., Schubert, M. Neuronal IGF-1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer’s disease.

Key Words: β-amyloid • longevity • insulin receptor substrate • brain • Tg2576 mice

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