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The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases

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Ben Haim, L. | Ceyzeriat, K. | Carrillo-de Sauvage, M.A. | Aubry, F. | Auregan, G. | Guillermier, M. | Ruiz, M. | Petit, F. | Houitte, D. | Faivre, E. | Vandesquille, M. | Aron-Badin, R. | Dhenain, M. | Deglon, N. | Hantraye, P. | Brouillet, E. | Bonvento, G. | Escartin, Carole

Edité par CCSD ; Society for Neuroscience -

International audience. 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 responsiblefor astrocyte reactivity in progressive pathological conditions such as ND. Inthis study, we examined whetherthe 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

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