Article

AGE

, Volume 35, Issue 1, pp 83-101

First online:

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

  • Oliver StöhrAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of Cologne
  • , Katharina SchilbachAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of Cologne
  • , Lorna MollAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of Cologne
  • , Moritz M. HettichAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneMolecular and Cellular Cognition Lab, German Centre for Neurodegenerative Diseases (DZNE)
  • , Susanna FreudeAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
  • , F. Thomas WunderlichAffiliated withCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneMax Planck Institute for Neurological Research
  • , Marianne ErnstAffiliated withCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneDepartment of Mouse Genetics and Metabolism, Institute for Genetics University of Cologne
  • , Johanna ZemvaAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of Cologne
  • , Jens C. BrüningAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneMax Planck Institute for Neurological ResearchDepartment of Mouse Genetics and Metabolism, Institute for Genetics University of Cologne
    • , Wilhelm KroneAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
    • , Michael UdelhovenAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneCenter for Endocrinology, Diabetes and Preventive Medicine, University of Cologne Email author 
    • , Markus SchubertAffiliated withCenter for Endocrinology, Diabetes and Preventive Medicine (CEDP), Center for Molecular Medicine Cologne (CMMC), University of CologneCologne excellence cluster in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of CologneCenter for Endocrinology, Diabetes and Preventive Medicine, University of Cologne Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

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 receptor Insulin-like growth factor-1 receptor β-Amyloid Alzheimer’s disease Tg2576 mice