Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jul;17(7):705-18.
doi: 10.1038/mp.2011.128. Epub 2011 Oct 18.

Regulation of the Phosphatase Calcineurin by Insulin-Like Growth Factor I Unveils a Key Role of Astrocytes in Alzheimer's Pathology

Affiliations

Regulation of the Phosphatase Calcineurin by Insulin-Like Growth Factor I Unveils a Key Role of Astrocytes in Alzheimer's Pathology

A M Fernandez et al. Mol Psychiatry. .

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.

Similar articles

See all similar articles

Cited by 23 articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback