Vessel-associated microglia contribute to blood-brain barrier disruption via a Notch-IL-1β axis in the diabetic brain

Diabetes mellitus (DM) is associated with central nervous system (CNS) complications, including cognitive impairment and an increased risk of neurodegenerative diseases. However, the cellular mechanisms underlying blood-brain barrier (BBB) disruption in the diabetic brain remain poorly understood. In this study, we investigated the contribution of microglia to diabetes-induced BBB dysfunction. Using a streptozotocin (STZ)-induced mouse model of type 1 diabetes, we observed increased BBB permeability and an accumulation of vessel-associated microglia. Transcriptomic analysis of isolated microglia revealed upregulation of genes associated with migration, angiogenesis, and vascular permeability, alongside activation of Notch signaling. We found that endothelial cell (EC)-derived CCL20, upregulated by TNF-α, promotes microglial migration via AKT signaling. Furthermore, direct interaction with ECs activates Notch signaling in microglia, inducing IL-1β expression and disrupting EC tight junctions. Treatment with minocycline attenuated microglial activation, restored endothelial Tjp1 expression, and reduced vascular leakage. These findings identify a novel microglia-EC signaling axis that contributes to BBB impairment in diabetes and suggest that targeting microglial activation may offer therapeutic potential for protecting neurovascular integrity in diabetic neuropathology.