Plasma proteins have a ticket to ride the blood-brain barrier

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Science Translational Medicine  15 Jul 2020:
Vol. 12, Issue 552, eabd3610
DOI: 10.1126/scitranslmed.abd3610


Analysis of labeled plasma proteins reveals a shift from receptor-mediated brain uptake to less specific transcytosis that occurs with aging.

The blood-brain barrier is commonly understood to restrict the passage of macromolecules from the periphery to the central nervous system, contributing to the brain’s status as a privileged organ. However, much of the historical understanding of this barrier is based on experiments with exogenous tracers, whereas the permeability of the native plasma proteome remained less clear. Now, Yang et al. have found that plasma proteins abundantly cross from the periphery to the brain in healthy young adult mice and that the nature of this transport changes with age from a receptor-mediated paradigm to a less specific transcytosis.

The authors labeled the mouse plasma proteome with a variety of small tags and visualized uptake of plasma in multiple cell types including neurons and microglia across brain regions in young healthy mice. Combining flow cytometry to measure plasma uptake with single-cell RNA sequencing in brain endothelial cells, they reported a detailed transcriptional pattern implicating an active and regulated transcytosis of plasma proteins across arterial, capillary, and venous segments. Comparison between young and aged mice revealed an increase in immunoglobulin G (IgG) uptake and a decrease in transport of IgG- and albumin-depleted plasma with age. Transcriptomic analysis suggested a decline in ligand-specific, receptor-mediated transcytosis and an increase in non-specific caveolar uptake. Further supporting this phenomenon as a tunable process, they identified alkaline phosphatase (ALPL) as a negative regulator of plasma uptake that was up-regulated with age and showed that pharmacologic inhibition of ALPL increased uptake of plasma as well as transferrin in aged mice.

These results reinforce the concept that the blood-brain barrier is less of a non-selective barrier and more of highly regulated organ that plays distinct physiological roles in brain health. As the authors suggest, the shift away from receptor-mediated transport with age may have important implications for understanding pathophysiology of neurodegenerative diseases. Perhaps most exciting is the demonstration that pharmacologic manipulation of ALPL increases plasma uptake preferentially in aged mice. Although further work is needed to harness the molecular and cellular specificity of this system, these findings bolster the idea that the blood-brain barrier represents a therapeutic target to regulate passage of macromolecules implicated in neurodegenerative and inflammatory conditions and to optimize delivery of systemically administered drugs for brain disorders.

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