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Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease

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Abstract

In brains from patients with Alzheimer’s disease (AD), expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), and insulin receptor substrate proteins is downregulated. A key step in the pathogenesis of AD is the accumulation of amyloid precursor protein (APP) cleavage products, β-amyloid (Aβ)1-42 and Aβ1–40. Recently, we and others have shown that central IGF-1 resistance reduces Aβ accumulation as well as Aβ toxicity and promotes survival. To define the role of IR in this context, we crossed neuron-specific IR knockout mice (nIR−/−) with Tg2576 mice, a well-established mouse model of an AD-like pathology. Here, we show that neuronal IR deficiency in Tg2576 (nIR−/−Tg2576) mice leads to markedly decreased Aβ burden but does not rescue premature mortality of Tg2576 mice. Analyzing APP C-terminal fragments (CTF) revealed decreased α-/β-CTFs in the brains of nIR−/−Tg2576 mice suggesting decreased APP processing. Cell based experiments showed that inhibition of the PI3-kinase pathway suppresses endosomal APP cleavage and decreases α- as well as β-secretase activity. Deletion of only one copy of the neuronal IGF-1R partially rescues the premature mortality of Tg2576 mice without altering total amyloid load. Analysis of Tg2576 mice expressing either a dominant negative or constitutively active form of forkhead box-O (FoxO)1 did not reveal any alteration of amyloid burden, APP processing and did not rescue premature mortality in these mice. Thus, our findings identified IR signaling as a potent regulator of Aβ accumulation in vivo. But exclusively decreased IGF-1R expression reduces AD-associated mortality independent of β-amyloid accumulation and FoxO1-mediated transcription.

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Acknowledgments

We thank Prof. Dr. R. Wiesner for critical discussion of the data and the manuscript. This work was supported by the Alzheimer Forschungsinitiative e.V. (to MS # 08813) and the Else-Kröner-Fresenius Stiftung (to MS #2010_A93) and Köln Fortune (to MS and KS)

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Authors and Affiliations

  1. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Kerpener Str 62, 50931, Cologne, Germany

    Oliver Stöhr, Katharina Schilbach, Lorna Moll, Moritz M. Hettich, Susanna Freude, Johanna Zemva, Jens C. Brüning, Wilhelm Krone, Michael Udelhoven & Markus Schubert

  2. Cologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    Susanna Freude, F. Thomas Wunderlich, Marianne Ernst, Jens C. Brüning, Wilhelm Krone, Michael Udelhoven & Markus Schubert

  3. Max Planck Institute for Neurological Research, Zülpicher Straße 47, 50674, Cologne, Germany

    F. Thomas Wunderlich & Jens C. Brüning

  4. Molecular and Cellular Cognition Lab, German Centre for Neurodegenerative Diseases (DZNE), 53175, Bonn, Germany

    Moritz M. Hettich

  5. Department of Mouse Genetics and Metabolism, Institute for Genetics University of Cologne, Zülpicher Strasse 47, 50674, Cologne, Germany

    Marianne Ernst & Jens C. Brüning

  6. Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, CMMC building 66, 5.012, Robert-Koch-Str. 21, 50931, Cologne, Germany

    Michael Udelhoven & Markus Schubert

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  1. Oliver Stöhr
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Correspondence to Michael Udelhoven or Markus Schubert.

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Oliver Stöhr, Katharina Schilbach, and Lorna Moll contributed equally to this work.

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Supplementary Fig. 1

a Mutant FoxO1 constructs. b Cloning strategy of FoxO1DN and FoxO1ADA mice, IRES-internal ribosomal entry site, and WSS westphal stop sequence. c Immunohistochemistry using antibodies against eGFP in Rosa FoxO1DN Syn-Cre mice and respective controls (JPEG 88 kb)

High-resolution image (TIFF 11697 kb)

Supplementary Fig. 2

Insulin-stimulated Akt and Erk-1/-2 phosphorylation is decreased in hippocampi from nIR−/− mice. Isolated hippocampi of WT and nIR−/− mice were stimulated with insulin (5 nM) for 10 min. Hippocampal lysates were subject to SDS-PAGE and Western blotting. Membranes were probed using antbodies against pAktser473, Akt, pErk-1/-2Thr202/Tyr204, and Erk-1/-2 (JPEG 13 kb)

High-resolution image (TIFF 1606 kb)

Supplementary Fig. 3

Characterization of nIR−/−Tg2576 mice and respective controls up to the age of 60 weeks. a Body weight from male and female animals. b Blood glucose levels from male and female animals. Data were assessed from 66 female (50 Tg2576 and 16 nIR−/−Tg2576) and 66 male mice (52 Tg2576 and 14 nIR−/−Tg2576) (JPEG 44 kb)

High-resolution image (TIFF 2198 kb)

Supplementary Fig. 4

Reduced IGF-1R expression and decreased IGF-1-stimulated Akt phosphorylation in isolated hippocampi from nIGF-R+/− mice. a Determination of the abundance of IGF-1Rs from hippocampal lysates of WT and nIGF-R+/− mice using Western blots. b Isolated hippocampi of WT and nIGF-R+/− mice were stimulated with IGF-1 (5 nM) for 10 min. Hippocampal lysates were subject to SDS-PAGE and Western blotting. Membranes were probed using antibodies against pAktser473 and Akt (JPEG 15 kb)

High-resolution image (TIFF 1666 kb)

Supplementary Fig. 5

Characterization of nIGF-R+/−Tg2576 mice and respective controls up to the age of 60 weeks. a Body weight from male and female animals. b Blood glucose levels from male and female animals. Data were assessed from 50 female (40 Tg2576 and 10 nIR−/−Tg2576) and 49 male mice (31 Tg2576 and 18 nIR−/−Tg2576) (JPEG 41 kb)

High-resolution image (TIFF 1930 kb)

Supplementary Fig. 6

Characterization of FoxO1ADATg2576 mice and respective controls up to the age of 60 weeks. a Body weight from male and female animals. b Blood glucose levels from male and female animals. Data were assessed from 50 female (37 Tg2576 and 13 FoxO1ADATg2576) and 39 male mice (37 Tg2576 and 2 FoxO1ADATg2576). c Western blots of hippocampal lysates for the IGF-1R, pAktser473, Akt, pErk-1/-2Thr202/Tyr204, and Erk-1/-2 from female WT, FoxO1ADATg2576, FoxO1ADA, and Tg2576 mice (n = 4 per genotype) (JPEG 36 kb)

High-resolution image (TIFF 2078 kb)

Supplementary Fig. 7

Characterization of FoxO1DNTg2576 mice and respective controls up to the age of 60 weeks. a Body weight from male and female animals. b Blood glucose levels from male and female animals. Data were assessed from 70 female (56 Tg2576 and 14 FoxO1DNTg2576) and 56 male mice (44 Tg2576 and 12 FoxO1DNTg2576). c Western blot analysis for IGF-1R, IR, pAktser473, Akt, pErk-1/-2Thr202/Tyr204, Erk-1/-2, and FoxO1 from hippocampal lysates of WT, FoxO1DNTg2576, FoxO1DN, and Tg2576 mice (n = 4 per genotype) (JPEG 38 kb)

High-resolution image (TIFF 2302 kb)

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Stöhr, O., Schilbach, K., Moll, L. et al. Insulin receptor signaling mediates APP processing and β-amyloid accumulation without altering survival in a transgenic mouse model of Alzheimer’s disease. AGE 35, 83–101 (2013). https://doi.org/10.1007/s11357-011-9333-2

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