Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA sequencing. Using this isolation technique, we found an enrichment in BVAC populations, including distinct subsets of endothelial and microglial cells. In CSD compared to non-stress, home-cage control, differential gene expression patterns disclosed biological pathways involving vascular dysfunction, vascular healing, and immune system activation. Overall, our work demonstrates a unique technique to study BVAC populations from fresh brain tissue and suggests that neurovascular dysfunction is a key driver of psychosocial stress-induced brain pathology.

IntroductionMutations in INPP5D, which encodes for the SH2‐domain‐containing inositol phosphatase SHIP‐1, have recently been linked to an increased risk of developing late‐onset Alzheimer's disease. While INPP5D expression is almost exclusively restricted to microglia in the brain, little is known regarding how SHIP‐1 affects neurobiology or neurodegenerative disease pathogenesis.MethodsWe generated and investigated 5xFAD Inpp5dfl/flCx3cr1Ert2Cre mice to ascertain the function of microglial SHIP‐1 signaling in response to amyloid beta (Aβ)‐mediated pathology.ResultsSHIP‐1 deletion in microglia led to substantially enhanced recruitment of microglia to Aβ plaques, altered microglial gene expression, and marked improvements in neuronal health. Further, SHIP‐1 loss enhanced microglial plaque containment and Aβ engulfment when compared to microglia from Cre‐negative 5xFAD Inpp5dfl/fl littermate controls.DiscussionThese results define SHIP‐1 as a pivotal regulator of microglial responses during Aβ‐driven neurological disease and suggest that targeting SHIP‐1 may offer a promising strategy to treat Alzheimer's disease.Highlights Inpp5d deficiency in microglia increases plaque‐associated microglia numbers. Loss of Inpp5d induces activation and phagocytosis transcriptional pathways. Plaque encapsulation and engulfment by microglia are enhanced with Inpp5d deletion. Genetic ablation of Inpp5d protects against plaque‐induced neuronal dystrophy.