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 Bois, Ryan Hsieh, Haley C. Cropper, Daniela Berdnik, Lulin Li, Elizabeth Y. Wang, Gavin M. Traber, Carolyn R. Bertozzi, Jian Luo, Michael P. Snyder, Joshua E. Elias, Stephen R. Quake, Michelle L. James and Tony Wyss-Coray ()
Additional contact information
Andrew C. Yang: Stanford University School of Medicine
Marc Y. Stevens: Stanford University School of Medicine
Michelle B. Chen: Stanford University School of Medicine
Davis P. Lee: Stanford University School of Medicine
Daniel Stähli: Stanford University School of Medicine
David Gate: Stanford University School of Medicine
Kévin Contrepois: Stanford University School of Medicine
Winnie Chen: Stanford University School of Medicine
Tal Iram: Stanford University School of Medicine
Lichao Zhang: Chan Zuckerberg Biohub
Ryan T. Vest: Stanford University School of Medicine
Aisling Chaney: Stanford University School of Medicine
Benoit Lehallier: Stanford University School of Medicine
Niclas Olsson: Stanford University School of Medicine
Haley Bois: Stanford University School of Medicine
Ryan Hsieh: Stanford University School of Medicine
Haley C. Cropper: Stanford University School of Medicine
Daniela Berdnik: Stanford University School of Medicine
Lulin Li: Stanford University School of Medicine
Elizabeth Y. Wang: Stanford University School of Medicine
Gavin M. Traber: Stanford University School of Medicine
Carolyn R. Bertozzi: Stanford University
Jian Luo: Stanford University School of Medicine
Michael P. Snyder: Stanford University School of Medicine
Joshua E. Elias: Chan Zuckerberg Biohub
Stephen R. Quake: Stanford University School of Medicine
Michelle L. James: Stanford University School of Medicine
Tony Wyss-Coray: Stanford University

Nature, 2020, vol. 583, issue 7816, 425-430

Abstract: 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.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2453-z Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:583:y:2020:i:7816:d:10.1038_s41586-020-2453-z

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2453-z

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().