Abstract
Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease.
Highlights
Astrocytes become reactive in virtually all diseases of the central nervous system (CNS)
The Janus Kinase 2 (JAK2)-Signal Transducer and Activator of Transcription 3 (STAT3) pathway controls astrocyte reactivity in Alzheimer’s disease (AD) mice To study whether the JAK2-STAT3 pathway controls astrocyte reactivity in AD, we inhibited this pathway by overexpressing its endogenous inhibitor Suppressor Of Cytokine Signaling 3 (SOCS3, [6]) in APP/PS1dE9 transgenic mice (APP)/PS1dE9 mice
We found that nuclear STAT3 levels in hippocampal astrocytes were higher in 9 month-old APP mice than in WT-GFP mice, indicating STAT3 activation
Summary
Astrocytes become reactive in virtually all diseases of the central nervous system (CNS). Astrocyte reactivity is classically defined by two hallmarks: cellular hypertrophy and overexpression of intermediate filament proteins. Attempts to block astrocyte reactivity globally, through knock-out of astrocyte intermediate filament proteins [32, 38] or inhibition of intracellular signaling cascades [22, 77] show inconsistent effects on AD pathological outcomes. Such discrepancies could stem from the low efficiency and selectivity of these approaches that only impact astrocyte morphological changes or have partial effects on astrocyte reactivity. To understand how reactive astrocytes contribute to AD, it is crucial to develop a new strategy that efficiently modulates all types of reactive astrocytes
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