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

Mol Psychiatry. 2012 Jul;17(7):705-18. doi: 10.1038/mp.2011.128. Epub 2011 Oct 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology*
  • Brain / drug effects
  • Brain / enzymology
  • Brain / metabolism
  • Brain / pathology
  • Calcineurin / physiology*
  • Calcineurin Inhibitors
  • Cells, Cultured
  • Disease Models, Animal
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor I / physiology*
  • Maze Learning / physiology
  • Mice
  • Mice, Transgenic
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Phosphorylation
  • Plaque, Amyloid / pathology*
  • Recognition, Psychology / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology


  • Calcineurin Inhibitors
  • Forkhead Box Protein O3
  • Forkhead Transcription Factors
  • FoxO3 protein, mouse
  • NF-kappa B
  • Peroxisome Proliferator-Activated Receptors
  • Tumor Necrosis Factor-alpha
  • Insulin-Like Growth Factor I
  • Calcineurin