Physiological blood–brain transport is impaired with age by a shift in transcytosis

Andrew C. Yang, Marc Y. Stevens, Michelle B. Chen, Davis P. Lee, Daniel Stähli, David Gate, Kévin Contrepois, Winnie Chen, Tal Iram, Lichao Zhang, Ryan T. Vest, Aisling Chaney, Benoit Lehallier, Niclas Olsson, Haley du Bois, Ryan Hsieh, Haley C. Cropper, Daniela Berdnik, Lulin Li, Elizabeth Y. WangGavin M. Traber, Carolyn R. Bertozzi, Jian Luo, Michael P. Snyder, Joshua E. Elias, Stephen R. Quake, Michelle L. James, Tony Wyss-Coray

Research output: Contribution to journalArticlepeer-review

224 Scopus citations

Abstract

The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1–3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Original languageEnglish
Pages (from-to)425-430
Number of pages6
JournalNature
Volume583
Issue number7816
DOIs
StatePublished - Jul 16 2020

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