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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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.
“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]
The entry of inflammatory cytokines and chemokines into the brain occurs through active transport or nonspecific caveolar transcytosis.
“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]
The number of samples for the single-cell sequencing studies was set using prior studies and preliminary experiments that confirmed sufficient BECs would be available for statistical analysis.
“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]
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Endothelial Cell Senescence Effect on the Blood-Brain Barrier in Stroke and Cognitive Impairment
Real, M. G. C., Falcione, S. R., Boghozian, R., Clarke, M., Todoran, R., Pierre, A. S., Zhang, Y., Joy, T., & Jickling, G. C. (2024) · Neurology · doi:10.1212/wnl.0000000000210063 · Cited by 56 · see citing works
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Association of microplastics in human cerebrospinal fluid with Alzheimer’s disease-related changes
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Self-citationDesigning peptide nanoparticles for efficient brain delivery
Duro‐Castaño, A., Leite, D. M., Forth, J., Deng, Y., Matias, D., Noble-Jesus, C., & Battaglia, G. (2020) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2020.10.001 · Cited by 52 · see citing works
Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit
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Bone-derived PDGF-BB drives brain vascular calcification in male mice
Wang, J., Fang, C., Noller, K., Wei, Z., Liu, G., Shen, K., Song, K., Cao, X., & Wan, M. (2023) · Journal of Clinical Investigation · doi:10.1172/jci168447 · Cited by 49 · see citing works
Pericytes Across the Lifetime in the Central Nervous System
Bennett, H. C., & Kim, Y. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.627291 · Cited by 47 · see citing works
Review of Design Considerations for Brain-on-a-Chip Models
Cameron, T., Bennet, T. J., Rowe, E. M., Anwer, M., Wellington, C. L., & Cheung, K. C. (2021) · Micromachines · doi:10.3390/mi12040441 · Cited by 48 · see citing works
A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
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Brain Delivery of Nanomedicines: Trojan Horse Liposomes for Plasmid DNA Gene Therapy of the Brain
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The Growing Class of Novel RNAi Therapeutics
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Self-citationCaveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke
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Structural and molecular basis of choline uptake into the brain by FLVCR2
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Current Update on Transcellular Brain Drug Delivery
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- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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