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.

Adenosine is a neuromodulator acting through inhibitory A₁ receptors (A₁Rs) and facilitatory A_2ARs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A₁Rs, but the source of the adenosine activating A_2ARs is unknown. We now show that ecto-5′-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A_2ARs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A_2ARs and proximity ligation assays confirmed the close proximity of CD73 and A_2ARs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A_2AR prodrug that requires CD73 metabolization to activate A_2ARs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A_2AR KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A_2AR KO mice, as well as upon pharmacological A_2AR blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A_2AR function. This study points to CD73 as a new target that can fine-tune A_2AR activity, and a novel therapeutic target to manipulate A_2AR-mediated control of striatal function and neurodegeneration.