Blocking C3d + /GFAP + A1 Astrocyte Conversion with Semaglutide Attenuates Blood-Brain Barrier Disruption in Mice after Ischemic Stroke

Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce the transformation of astrocytes into a neurotoxic A1 phenotype, exacerbating brain injury. However, the effect of A1 astrocytes on the BBB dysfunction after stroke is unknown. Adult male ICR mice (n=97) were subjected to 90-minute transient middle cerebral artery occlusion (tMCAO). Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes in astrocytes over time after tMCAO. The glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into mice to inhibit A1 astrocytes. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were evaluated. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocyte-induced BBB dysfunction. Astrocytic C3d expression was increased, while expression of S100A10 was decreased in the first two weeks after tMCAO, reflecting a shift in the astrocytic phenotype. Semaglutide treatment reduced the expression of CD16/32 in microglia and C3d in astrocytes after ischemic stroke (