Atlas of Brain-Permeable Blood Proteins Links Neuroprotection to Alzheimer's Risk Genes [bulk_RNAseq_astrocyte]

The blood-brain barrier (BBB) is a highly selective interface that traditionally has been seen as restricting blood-borne substances from entering the brain. Despite its essential role in brain health and disease, the extent and functional impact of physiological blood-to-brain protein transport remain largely unexplored. Here, we use a combination of bioorthogonal chemistries, blood proteome labeling, and mass spectrometry to discover the repertoire of BBB-permeable proteins in healthy mice. We discovered that the brain vasculature actively samples hundreds of diverse circulatory proteins under physiological conditions. Many of these proteins accumulate in the brain, showing distinct enrichment patterns across both functional protein classes and anatomical brain regions. In models of neuroinflammatory and neurodegenerative diseases, the composition of BBB-permeable proteins changed significantly, implicating dysregulated protein transport in disease pathogenesis. Notably, single-injection validation experiments revealed that BBB-permeable proteins exhibit cell type-specific targeting to neurons, astrocytes, or microglia, suggesting specialized functional roles. Focusing on apolipoprotein A1 (APOA1), we demonstrate its entry via brain endothelial SCARB1 receptor, its selective accumulation in astrocytes and its interaction with the ABCA1 receptor—a critical AD risk gene that also binds APOE, the strongest genetic risk factor for late-onset Alzheimer's disease. This peripheral-central interaction promotes cholesterol efflux in astrocytes and protects neuronal synapses from degeneration. Overall, our study redefines the BBB as a dynamic conduit for the transport of specific, neuroprotective circulatory proteins into the healthy brain and establishes a molecular link between peripheral factors and Alzheimer's risk genes.