Cited by 218Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

Freude, Susanna, Hettich, Moritz M., Schumann, Christina, Stöhr, Oliver, Koch, Linda, Köhler, Christoph, Udelhoven, Michael, Leeser, Uschi +7 more·2009·The FASEB Journal

Abstract

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., Stohr, O., Koch, L., Kohler, C., Udelhoven, M., Leeser, U., Müller, M., Kubota, N., Kadowaki, T., Krone, W., Schroder, H., Bruning, J. C., Schubert, M. Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease. FASEB J . 23, 3315–3324 (2009). www.fasebj.org

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Crossref · 10.1096/fj.09-132043

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  • Knockout of Irs2 or the IGF-1 receptor can reduce cognitive impairment, neurodegeneration and premature mortality in mouse models of Alzheimer's disease.

    “Similarly, knockout of Irs2 or the IGF-1 receptor can reduce cognitive impairment, neurodegeneration and premature mortality in mouse models of Alzheimer’s disease (71,72).”

    From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [71]

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Authors
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., Schroder, H., Brüning, J. C., & Schubert, M.
Affiliations
  • University of Cologne (DE)
  • The University of Tokyo (JP)
  • Department II of Anatomy University of Cologne Cologne Germany
Corresponding author
Schubert, Markus
Venue
The FASEB Journal
Publisher
Wiley
Published
2009-06
Volume
23
Issue
10
Pages
3315-3324
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
OpenAlex
W2134406000
Cited by
218
References
61
Citations by year
2026: 3 · 2025: 5 · 2024: 12 · 2023: 16 · 2022: 13 · 2021: 8 · 2020: 9 · 2019: 10 · 2018: 11 · 2017: 7 · 2016: 16 · 2015: 10 · 2014: 26 · 2013: 15 · 2012: 21
FWCI
12.63
Type
journal article
Language
en
Open access
closed
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed (publishedVersion)
  • OPUS (Augsburg University) (submittedVersion)
Funders
  • Fritz Thyssen Stiftung (AZ 10.06.2.209)
  • Deutsche Forschungsgemeinschaft (Br-1492-7)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, IGF-1 resistance, IGF-1 receptor, insulin receptor substrate 2, insulin/IGF-1 signaling, amyloid-beta deposition, amyloid precursor protein, Tg2576 mice, premature mortality, hippocampus, APP processing, neuroprotection
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Female, Insulin-Like Growth Factor I, Male, Mice, Mutant Strains, Neurons, Amyloid beta-Peptides, Receptor, IGF Type 1, Mice, Insulin Receptor Substrate Proteins

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