title: The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases.
abstract: Astrocyte reactivity is a hallmark of neurodegenerative diseases (ND), but its effects on disease outcomes remain highly debated. Elucidation of the signaling cascades inducing reactivity in astrocytes during ND would help characterize the function of these cells and identify novel molecular targets to modulate disease progression. The Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway is associated with reactive astrocytes in models of acute injury, but it is unknown whether this pathway is directly responsible for astrocyte reactivity in progressive pathological conditions such as ND. In this study, we examined whether the JAK/STAT3 pathway promotes astrocyte reactivity in several animal models of ND. The JAK/STAT3 pathway was activated in reactive astrocytes in two transgenic mouse models of Alzheimer's disease and in a mouse and a nonhuman primate lentiviral vector-based model of Huntington's disease (HD). To determine whether this cascade was instrumental for astrocyte reactivity, we used a lentiviral vector that specifically targets astrocytes in vivo to overexpress the endogenous inhibitor of the JAK/STAT3 pathway [suppressor of cytokine signaling 3 (SOCS3)]. SOCS3 significantly inhibited this pathway in astrocytes, prevented astrocyte reactivity, and decreased microglial activation in models of both diseases. Inhibition of the JAK/STAT3 pathway within reactive astrocytes also increased the number of huntingtin aggregates, a neuropathological hallmark of HD, but did not influence neuronal death. Our data demonstrate that the JAK/STAT3 pathway is a common mediator of astrocyte reactivity that is highly conserved between disease states, species, and brain regions. This universal signaling cascade represents a potent target to study the role of reactive astrocytes in ND.
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Lucile
authors: http://orcid.org/0000-0002-3652-5736
authors: L
authors: Ben Haim
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Kelly
authors: http://orcid.org/0000-0003-4941-5226
authors: K
authors: Ceyzériat
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Maria Angeles
authors: http://orcid.org/0000-0002-3312-5956
authors: MA
authors: Carrillo-de Sauvage
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Fabien
authors: F
authors: Aubry
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Gwennaëlle
authors: G
authors: Auregan
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Martine
authors: M
authors: Guillermier
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Marta
authors: M
authors: Ruiz
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Fanny
authors: F
authors: Petit
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Diane
authors: D
authors: Houitte
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Emilie
authors: E
authors: Faivre
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Matthias
authors: M
authors: Vandesquille
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Romina
authors: R
authors: Aron-Badin
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Marc
authors: M
authors: Dhenain
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Nicole
authors: N
authors: Déglon
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Philippe
authors: P
authors: Hantraye
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Emmanuel
authors: E
authors: Brouillet
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France.
authors: Gilles
authors: G
authors: Bonvento
authors: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), F-92260 Fontenay-aux-Roses, France, and Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, UMR 9199, Neurodegenerative Diseases Laboratory, F-92260 Fontenay-aux-Roses, France carole.escartin@cea.fr.
authors: Carole
authors: http://orcid.org/0000-0003-3613-4118
authors: C
authors: Escartin
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001253:Astrocytes; D003576:Electron Transport Complex IV / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000503:physiopathology*; D053612:Janus Kinases; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D003576:Electron Transport Complex IV; D053612:Janus Kinases
keywords: SOCS3; STAT3; animal models; lentiviral vector; neurodegenerative diseases; reactive astrocytes