Integrative multi-omic profiling of adult mouse brain endothelial cells and potential implications in Alzheimer’s disease

The blood-brain barrier (BBB) is primarily manifested by a variety of physiological properties of brain endothelial cells (ECs), but the molecular foundation for these properties remains incompletely clear. Here, we generate a comprehensive molecular atlas of adult brain ECs using acutely purified mouse ECs and integrated multi-omics. Using RNA sequencing (RNA-seq) and proteomics, we identify the transcripts and proteins selectively enriched in brain ECs and demonstrate that they are partially correlated. Using single-cell RNA-seq, we dissect the molecular basis of functional heterogeneity of brain ECs. Using integrative epigenomics and transcriptomics, we determine that TCF/LEF, SOX, and ETS families are top-ranked transcription factors regulating the BBB. We then validate the identified brain-EC-enriched proteins and transcription factors in normal mouse and human brain tissue and assess their expression changes in mice with Alzheimer’s disease. Overall, we present a valuable resource with broad implications for regulation of the BBB and treatment of neurological disorders. [Display omitted] •Adult mouse brain-EC-enriched transcripts and proteins show a partial correlation•TCF/LEF1, SOX, and ETS are top-ranked transcription factors (TFs) regulating the BBB•Proteins and TFs enriched in mouse brain ECs are largely conserved in humans•Brain-EC-enriched proteins and LEF1 are reduced in mice with Alzheimer’s disease The blood-brain barrier function critically regulates brain health and disease. Yu et al. produce a comprehensive molecular atlas of adult mouse brain endothelial cells using integrated multi-omics analyses. They then validate their findings in normal mouse and human brain tissue and explore potential relevance to Alzheimer’s disease in mice.