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Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology

Molecular Psychiatry volume 17, pages 705–718 (2012)Cite this article

Abstract

Whether insulin-like growth factor I (IGF-I) signaling in Alzheimer's disease (AD) is beneficial or detrimental remains controversial. We now show that a competitive regulation by IGF-I of the phosphatase calcineurin in reactive, but not in quiescent astrocytes drives Alzheimer's pathology. Calcineurin de-phosphorylates the transcription factor Foxo3 in response to tumor necrosis factor-α (TNFα), an inflammatory cytokine increased in AD, activating nuclear factor-κB (NFκB) inflammatory signaling in astrocytes. In turn, IGF-I inactivates and displaces Foxo3 from calcineurin in TNFα-stimulated astrocytes by recruiting the transcription factor peroxisome proliferator-activated receptor-γ, and NFκB signaling is inhibited. This antagonistic mechanism reversibly drives the course of the disease in AD mice, even at advanced stages. As hallmarks of this calcineurin/Foxo3/NFκB pathway are present in human AD brains, treatment with IGF-I may be beneficial by antagonizing it.

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Acknowledgements

We are thankful to A Zambrano, C Hernandez Capitán, M Garcia, I Alvarez and L Guinea for technical support. This work was funded by Spanish Ministry of Science (SAF2007-60051) and by CIBERNED.

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  1. S Jimenez and M Mecha: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Neuroendocrinology, Cajal Institute and CIBERNED, Madrid, Spain

    A M Fernandez, D Dávila & I Torres-Aleman

  2. Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Seville and CIBERNED, Seville, Spain

    S Jimenez & J Vitorica

  3. Laboratory of Neuroimmunology, Cajal Institute, Madrid, Spain

    M Mecha & C Guaza

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Correspondence to I Torres-Aleman.

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ITA has shares in a spin-off company devoted to the use of IGF-I in neurodegenerative diseases.

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Fernandez, A., Jimenez, S., Mecha, M. et al. Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology. Mol Psychiatry 17, 705–718 (2012). https://doi.org/10.1038/mp.2011.128

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