Brain endothelial cells are exquisite sensors of age-related circulatory cues

Abstract

Brain endothelial cells (BECs) are key elements of the blood-brain barrier (BBB), protecting the brain from pathogens and restricting access to circulatory factors. Recent studies have demonstrated that the circulatory environment can modulate brain aging, yet, the underlying processes remain largely unknown. Given the BBBs intermediary position, we hypothesized that BECs sense, adapt to, and relay signals between the aging blood and brain. We sequenced single endothelial cells from the hippocampus--a brain region key to learning, memory, and neurogenesis-- of healthy young and aged mice as well as post-exposure to inflammatory and age-related circulatory factors. We discovered that aged capillary BECs, compared with arterial and venous cells, exhibit the greatest transcriptional changes, upregulating innate immunity, antigen presentation, TGF-{beta} signaling and oxidative stress response pathways. Remarkably, short-term infusions of aged plasma into young mice recapitulated key aspects of this aging transcriptome, while infusions of young plasma into aged mice reversed select aging signatures, essentially rejuvenating the BBB endothelium transcriptome. We identify candidate pathways mediating blood-borne brain rejuvenation by comparing age-upregulated genes with those modulated by plasma exposure. Together, these findings suggest that the transcriptional age of BECs is exquisitely sensitive to age-related circulatory cues and pinpoint the BBB itself as a promising therapeutic target to treat brain disease.\n\nHighlightsO_LISingle-cell RNA sequencing of brain endothelial cells (BECs) reveals transcriptional segmentation into distinct arterial, capillary, and venous identities with age and experimental interventions\nC_LIO_LIChanges with age are heterogenous across vessel segments, with aged capillaries enriched in signatures of innate immunity, TGF-{beta} and VEGF signaling, hypoxia and oxidative stress\nC_LIO_LIBECs sense and respond transcriptionally to diverse circulatory cues: inflammatory, proaging, or rejuvenating\nC_LIO_LIAged plasma exposure recapitulates--and young plasma reverses--key transcriptomic signatures of normal BEC aging\nC_LIO_LIBEC response to aged and young plasma reveals cell non-autonomous mechanisms of blood-brain-barrier aging\nC_LI