AGE

, Volume 35, Issue 1, pp 83–101

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

  • Oliver Stöhr
  • Katharina Schilbach
  • Lorna Moll
  • Moritz M. Hettich
  • Susanna Freude
  • F. Thomas Wunderlich
  • Marianne Ernst
  • Johanna Zemva
  • Jens C. Brüning
  • Wilhelm Krone
  • Michael Udelhoven
  • Markus Schubert
Article

DOI: 10.1007/s11357-011-9333-2

Cite this article as:
Stöhr, O., Schilbach, K., Moll, L. et al. AGE (2013) 35: 83. doi:10.1007/s11357-011-9333-2

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.

Keywords

Insulin receptorInsulin-like growth factor-1 receptorβ-AmyloidAlzheimer’s diseaseTg2576 mice

Supplementary material

11357_2011_9333_Fig8_ESM.jpg (88 kb)
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)

11357_2011_9333_MOESM1_ESM.tif (11.4 mb)
High-resolution image (TIFF 11697 kb)
11357_2011_9333_Fig9_ESM.jpg (13 kb)
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)

11357_2011_9333_MOESM2_ESM.tif (1.6 mb)
High-resolution image (TIFF 1606 kb)
11357_2011_9333_Fig10_ESM.jpg (45 kb)
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)

11357_2011_9333_MOESM3_ESM.tif (2.1 mb)
High-resolution image (TIFF 2198 kb)
11357_2011_9333_Fig11_ESM.jpg (15 kb)
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)

11357_2011_9333_MOESM4_ESM.tif (1.6 mb)
High-resolution image (TIFF 1666 kb)
11357_2011_9333_Fig12_ESM.jpg (41 kb)
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)

11357_2011_9333_MOESM5_ESM.tif (1.9 mb)
High-resolution image (TIFF 1930 kb)
11357_2011_9333_Fig13_ESM.jpg (36 kb)
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)

11357_2011_9333_MOESM6_ESM.tif (2 mb)
High-resolution image (TIFF 2078 kb)
11357_2011_9333_Fig14_ESM.jpg (39 kb)
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)

11357_2011_9333_MOESM7_ESM.tif (2.2 mb)
High-resolution image (TIFF 2302 kb)

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Oliver Stöhr
    • 1
  • Katharina Schilbach
    • 1
  • Lorna Moll
    • 1
  • Moritz M. Hettich
    • 1
    • 4
  • Susanna Freude
    • 1
    • 2
  • F. Thomas Wunderlich
    • 2
    • 3
  • Marianne Ernst
    • 2
    • 5
  • Johanna Zemva
    • 1
  • Jens C. Brüning
    • 1
    • 2
    • 3
    • 5
  • Wilhelm Krone
    • 1
    • 2
  • Michael Udelhoven
    • 1
    • 2
    • 6
  • Markus Schubert
    • 1
    • 2
    • 6
  1. 1.Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC)University of CologneCologneGermany
  2. 2.Cologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD)University of CologneCologneGermany
  3. 3.Max Planck Institute for Neurological ResearchCologneGermany
  4. 4.Molecular and Cellular Cognition LabGerman Centre for Neurodegenerative Diseases (DZNE)BonnGermany
  5. 5.Department of Mouse Genetics and MetabolismInstitute for Genetics University of CologneCologneGermany
  6. 6.Center for Endocrinology, Diabetes and Preventive MedicineUniversity of CologneCologneGermany