title: Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-β-Induced Neuronal Death.
abstract: Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer's disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD-associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against Aβ-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the Aβ-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Aβ levels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted.
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.|CIBERNED, Madrid, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Fernandez
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Hervas
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.|CIBERNED, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Dominguez-Fraile
authors.affiliation: CIBERNED, Madrid, Spain.|IBIS, CSIC-Universidad de Sevilla, Sevilla, Spain.
authors.forename: Victoria Navarro
authors.initials: VN
authors.lastname: Garrido
authors.affiliation: GBMI, Universitat Politécnica de Catalunya, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Gutierrez
authors.affiliation: Allinky Biopharma, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vega
authors.affiliation: CIBERNED, Madrid, Spain.|IBIS, CSIC-Universidad de Sevilla, Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
authors.affiliation: GBMI, Universitat Politécnica de Catalunya, Barcelona, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Perez
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.|CIBERNED, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Torres Aleman
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D000071316:Forkhead Box Protein O3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019703:Calcineurin
keywords: Alzheimer’s disease; FOXO; astrocytes; calcineurin; decoy compounds