The blood–brain barrier has gained notoriety for its low permeability to macromolecules and protein therapeutic agents. Here, using the whole blood plasma proteome as a discovery tool, Tony Wyss-Coray, Andrew Yang et al. directly visualize plasma proteins readily permeating the healthy adult mouse brain parenchyma. They demonstrate that this process is highly regulated by transcriptional programs unique to the brain endothelium, and uptake varies considerably by vessel zones (venous cells, arterial cells and capillaries). With age, many of the regulators of plasma uptake are downregulated, resulting in a shift from receptor-mediated to nonspecific caveolar transcytosis into the brain. This shift can be partially mitigated by inhibition of a predicted negative regulator of transcytosis, the alkaline phosphatase ALPL. These findings provide a molecular basis for blood–brain barrier disruption and increased ‘leakiness’ to neurotoxic plasma proteins with age and neurodegenerative disease. The authors discuss how dysregulated entry of neurotoxic proteins could trigger neuroinflammation, linking age-related vascular dysfunction and reactive gliosis, and how their findings may help to overcome challenges in central nervous system drug delivery for age-related neurodegenerative disease.
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