ACTIVATION OF THE JAK/STAT3 PATHWAY IN ASTROCYTES IN ALZHEIMER'S AND HUNTINGTON'S DISEASE

Introduction: Astrocyte reactivity, characterized by molecular, morphological, and functional changes, is a hallmark of neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Huntington's disease (HD). Reactive astrocytes, which become hypertrophic and upregulate intermediate filament proteins like GFAP and vimentin, are frequently observed near amyloid plaques in AD, the striatum, and the cortex in HD. The involvement of the Janus kinase/signal transducer and activator of the transcription 3 (JAK/STAT3) pathway in astrocyte reactivity has been well-documented in models of acute injury. Still, its role in chronic conditions like NDs remains unclear. This study explores whether the JAK/STAT3 pathway directly induces astrocyte reactivity in several AD and HD animal models and assesses the impact of inhibiting this pathway on astrocyte behavior and disease pathology.

Key Findings: In this study, the JAK/STAT3 pathway was found to be activated in reactive astrocytes in two transgenic mouse models of AD (APP/PS1dE9 and 3xTg-AD) and a lentiviral vector-based model of HD in mice and nonhuman primates. In APP/PS1dE9 mice, STAT3 accumulated in the nucleus of GFAP+ and vimentin+ astrocytes around amyloid plaques, with the number of GFAP+ astrocytes expressing nuclear STAT3 being significantly higher than in wild-type (WT) controls (p = 0.0235). Similarly, in 3xTg-AD mice, the number of astrocytes coexpressing GFAP and nuclear STAT3 was more than ten times higher than in age-matched WT mice (p < 0.0001). In the HD model, four times more nuclear STAT3+/GFAP+ astrocytes were found in the Htt82Q striatum compared to the Htt18Q striatum (p = 0.0004).

To investigate the functional role of the JAK/STAT3 pathway, the researchers used a lentiviral vector to overexpress SOCS3, an endogenous inhibitor of the pathway, specifically in astrocytes. In both AD and HD models, SOCS3 overexpression significantly reduced nuclear STAT3 accumulation and astrocyte reactivity. In 3xTg-AD mice, SOCS3 expression reduced the GFAP+ area by 73% (p = 0.0827) and the number of GFP+ astrocytes coexpressing GFAP by 94% (p = 0.0149). In the HD model, SOCS3 reduced the GFAP+ area by 86% (p = 0.0035) and the number of GFP+/GFAP+ astrocytes by 87% (p = 0.0072).

Innovative Tools: The researchers employed advanced methods to analyze astrocyte reactivity and the effects of JAK/STAT3 pathway inhibition. These included immunofluorescence to detect pathway activation and Western blotting to measure protein levels. They used fluorescence-activated cell sorting (FACS) to monitor cell division and transfection efficiency and employed TEER measurements to evaluate blood-brain barrier integrity. Additionally, they utilized stereotaxic injections to deliver lentiviral vectors specifically to astrocytes, ensuring precise targeting and effective inhibition of the JAK/STAT3 pathway.

Role of the JAK/STAT3 Pathway: The JAK/STAT3 pathway was shown to be a universal mediator of astrocyte reactivity across different models and species. Activation of this pathway led to the nuclear localization of STAT3 in astrocytes, a marker used to indicate pathway activation. The inhibition of this pathway by SOCS3 significantly reduced astrocyte reactivity, confirming that the JAK/STAT3 pathway is crucial for maintaining the reactive state of astrocytes in NDs. The absence of NF-κB pathway activation, evidenced by unchanged IκBα levels in both AD and HD models, further emphasized the central role of the JAK/STAT3 pathway in astrocyte reactivity.

Neuroinflammation and Huntingtin Aggregates: Inhibiting astrocyte reactivity through SOCS3 overexpression also had notable effects on neuroinflammation and huntingtin aggregates in the HD model. SOCS3 expression reduced microglial activation, as indicated by a 38% decrease in the IBA1+ area in the HD model (p = 0.0397). At the transcriptional level, SOCS3 normalized the expression of neuroinflammatory markers such as aif1 (iba1), itgam (CD11b), and ccl2, which were significantly upregulated by Htt82Q (p < 0.05). However, SOCS3 overexpression led to a 1.5-fold increase in EM48+ huntingtin aggregates (p = 0.0409), suggesting that reactive astrocytes may play a role in managing protein aggregation.

Conclusions: This study identifies the JAK/STAT3 pathway as a critical mediator of astrocyte reactivity in neurodegenerative diseases. By demonstrating that inhibition of this pathway can prevent astrocyte reactivity without affecting neuronal survival, the findings suggest potential therapeutic strategies targeting this pathway to modulate disease progression. The results highlight the complexity of astrocyte functions in NDs, where reactive astrocytes may simultaneously contribute to neuroinflammation and protein aggregation. Future research should focus on understanding the precise mechanisms by which astrocytes influence neuronal health and how these pathways can be manipulated for therapeutic benefit.

Join the Discussion: We encourage readers to explore the implications of these findings for treating neurodegenerative diseases. How might targeting the JAK/STAT3 pathway influence therapeutic strategies for diseases such as Alzheimer's and Huntington's? Share your thoughts and insights in the comments section below.

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Original Research: The original research, "The JAK/STAT3 pathway is a common inducer of astrocyte reactivity in Alzheimer's and Huntington's diseases," can be found on PubMed here.