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Physiological blood–brain transport is impaired with age by a shift in transcytosis
Open accessAbstract
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 permeability 1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins 4,5. 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.
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“To determine the samples size for the single-cell sequencing studies, we used previous studies13,26 and performed preliminary studies to confirm that we will obtain enough BECs for statistical analysis (not included in the manuscript).”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [26]
In the citing paper
“BBB permeability becomes less selective with aging because of a loss of tight junctions and a shift from tightly regulated receptor-mediated transcytosis toward nonspecific transcytosis of plasma proteins (136, 137).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [137]
In the citing paper
“In parallel, the entry of inflammatory cytokines and chemokines occurs through active transport or nonspecific caveolar transcytosis (137, 142).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [137]
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“However, how transcytosis is constantly modified due to temporal or chronic changes in the brain homeostasis and the peripheral environment, especially during aging or pathophysiological conditions, still raises many questions [28,59].”
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Metadata
- Authors
- Yang, A. C., Stevens, M. Y., Chen, M. B., Lee, D. P., Stähli, D., Gate, D., Contrepois, K., Chen, W., Iram, T., Zhang, L., Vest, R. T., Chaney, A., Lehallier, B., Olsson, N., du Bois, H., Hsieh, R., Cropper, H. C., Berdnik, D., Li, L., Wang, E. Y., Traber, G. M., Bertozzi, C. R., Luo, J., Snyder, M. P., Elias, J. E., Quake, S. R., James, M. L., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- VA Palo Alto Health Care System (US)
- ORCID
- Yang, Andrew C.
- Stevens, Marc Y.
- Gate, David
- Contrepois, Kévin
- Chen, Winnie
- Iram, Tal
- Zhang, Lichao
- Chaney, Aisling
- Lehallier, Benoit
- Olsson, Niclas
- Cropper, Haley C.
- Berdnik, Daniela
- Li, Lulin
- Wang, Elizabeth Y.
- Traber, Gavin M.
- Bertozzi, Carolyn R.
- Luo, Jian
- Snyder, Michael P.
- Elias, Joshua E.
- Quake, Stephen R.
- James, Michelle L.
- Wyss-Coray, Tony
- Venue
- Nature
- Published
- 2020-07-01
- Volume
- 583
- Issue
- 7816
- Pages
- 425-430
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8331074
- OpenAlex
- W3039975419
- Cited by
- 477
- References
- 96
- Citations by year
- 2026: 63 · 2025: 91 · 2024: 83 · 2023: 69 · 2022: 75 · 2021: 74 · 2020: 22
- FWCI
- 23.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- American Heart Association (19PABHI34580007)
- Glenn Foundation for Medical Research
- NOMIS Stiftung
- National Institutes of Health (1s10od025091-01, T32-AG0047126)
- Wu Tsai Neurosciences Institute, Stanford University
- National Institute on Aging (RF1AG059694, DP1AG053015, T32AG047126, P30AG066515)
- National Human Genome Research Institute (P50HG007735)
- National Cancer Institute (R01CA200423)
- National Institute of General Medical Sciences (T32GM099608, GM059907, R01GM059907)
- National Center for Research Resources (1S10OD01227601)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- blood-brain barrier, brain aging, transcytosis, receptor-mediated transport, pericyte coverage, ALPL, transferrin, transferrin receptor, plasma proteome, brain endothelium, BBB dysfunction, brain drug delivery
- MeSH terms
- Aging, Alkaline Phosphatase, Animals, Antibodies, Biological Transport, Blood Proteins, Blood-Brain Barrier, Brain, Health, Humans, Male, Mice, Inbred C57BL, Plasma, Receptors, Transferrin, Transcription, Genetic, Transferrin, Drug Delivery Systems, Proteome, Mice, Transcytosis
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