title: Regulation of the phosphatase calcineurin by insulin-like growth factor I unveils a key role of astrocytes in Alzheimer's pathology.
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.
authors: Laboratory of Neuroendocrinology, Cajal Institute and CIBERNED, Madrid, Spain.
authors: A M
authors: AM
authors: Fernandez
authors: S
authors: S
authors: Jimenez
authors: M
authors: M
authors: Mecha
authors: D
authors: D
authors: Dávila
authors: C
authors: C
authors: Guaza
authors: J
authors: J
authors: Vitorica
authors: I
authors: I
authors: Torres-Aleman
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000473:pathology*; D021641:Recognition, Psychology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology
chemical_list: D065095:Calcineurin Inhibitors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D016328:NF-kappa B; D047492:Peroxisome Proliferator-Activated Receptors; D014409:Tumor Necrosis Factor-alpha; D007334:Insulin-Like Growth Factor I; D019703:Calcineurin