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

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          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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