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.

Natural product HTP screening for attenuation of cytokine-induced neutrophil chemo attractants (CINCs) and NO2− in LPS/IFNγ activated glioma cells

“…These are known to include specific targets such as janus kinase/signal transducer and activator of transcription (JAK/STAT) (Ben Haim, Carrillo-de Sauvage, 2015a, Ben Haim et al, 2015b, Wang et al, 2015b), nuclear Factor of Kappa light polypeptide gene enhancer in B-cells (NF-κB), calcineurin, Mitogen-Activated Protein Kinases (MAPKs) (Ben Haim, Carrillo-de Sauvage, 2015a) or Notch1-STAT3-ETB (LeComte et al, 2015). These are the indirect controls account for biological events such as induction of iNOS, release of NO, MCP-1 and CINCS.…”

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

“…Astrocytic glutamate uptake is defective in the R6/2 HD mouse model, where levels of EAAT2 are reduced, leading to increase in striatal extracellular glutamate and excitotoxicity (Maragakis and Rothstein, 2001). Recently, astrocytic Kir4.1 was reported to be significantly downregulated in HD mouse models, independently of overt astrogliosis (Ben Haim et al, 2015). Decreased expression of Kir4.1 K + channels leads to elevated striatal extracellular K + in vivo which can result in depolarization of neurons.…”

The choreography of neuroinflammation in Huntington's disease

“…In partial contrast with these observations is the fact that striatal injection of adeno-associated virus (AAV)-encoding dominant negative TNF did not rescue MSNs in the YAC128 model of HD (i.e., containing a yeast artificial chromosome expressing the full-length human HTT gene containing 128 CAG repeat expansion in exon-1) [83]. Using a lentivirus system to deliver control or mutant Htt N terminal proteins to all cells of the brain, the Janus kinase (JAK)/STAT3 pathway was found to play a prominent role in astrocyte activation in mice and monkeys [84] JAK/STAT3 signaling is commonly triggered by IL-6, a cytokine produced in HD brains by microglia [5]. These findings are consistent with the possibility that astrocytes amplify pro-inflammatory signaling initiated by microglia.…”