Activated endothelial cells induce a distinct type of astrocytic reactivity

Reactive astrogliosis is a universal response of astrocytes to abnormal events and injuries. Studies have shown that proinflammatory microglia can polarize astrocytes (designated A1 astrocytes) toward a neurotoxic phenotype characterized by increased Complement Component 3 (C3) expression. It is still unclear if inflammatory stimuli from other cell types may also be capable of inducing a subset of C3⁺ neurotoxic astrocytes. Here, we show that a subtype of C3⁺ neurotoxic astrocytes is induced by activated endothelial cells that is distinct from astrocytes activated by microglia. Furthermore, we show that endothelial-induced astrocytes have upregulated expression of A1 astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial-induced astrocytes are Decorin-positive and are associated with vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings demonstrate the existence of potentially extensive and subtle functional diversity of C3⁺-reactive astrocytes.