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Title

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

AuthorsFernández García, Ana María ; Jiménez, S.; Mecha, Miriam ; Dávila, D.; Guaza, Carmen ; Vitorica, Javier ; Torres Alemán, Ignacio
Issue Date2012
PublisherNature Publishing Group
CitationMolecular Psychiatry 17: 705- 718 (2012)
AbstractWhether 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 NFB 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. © 2012 Macmillan Publishers Limited All rights reserved.
URIhttp://hdl.handle.net/10261/61085
DOI10.1038/mp.2011.128
Identifiersdoi: 10.1038/mp.2011.128
issn: 1359-4184
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