Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1
Open accessAbstract
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
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Age-related inflammatory factors in blood, such as TNF-α, can further increase BBB permeability by suppressing the expression of tight junctions and enhancing brain endothelial cell adhesion, ultimately increasing neuroinflammation.
“Age-related inflammatory factors in blood, such as TNF-α, can further increase BBB permeability by suppressing the expression of tight junctions and enhancing brain endothelial cell adhesion, ultimately increasing neuroinflammation (138–140).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [140]
Circulating TNF-α, IL-1β, and IL-6 bind to receptors in endothelial cells and induce the expression of cellular adhesion proteins (e.g., VCAM1) that further promote inflammation by triggering NF-κB signaling.
“Circulating TNF-α, IL-1β, and IL-6 bind to receptors in endothelial cells and induce the expression of cellular adhesion proteins (e.g., VCAM1) that further promote inflammation by triggering NF-κB signaling (Figure 3) (136, 140, 141).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [140]
This process facilitates tethering of circulating myeloid cells to the brain endothelia, augmenting the intravascular inflammatory state and promoting the activation of microglia.
“This process facilitates tethering of circulating myeloid cells to the brain endothelia, augmenting the intravascular inflammatory state and promoting the activation of microglia, the brain’s innate immune cell (140).”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [140]
Vascular cell adhesion molecule 1 and acid sphingomyelinase play a crucial role in destroying the cerebrovascular system, while cyclophilin A decreases the levels of synapse-related proteins such as the NMDAR subunit NR2B and synaptophysin.
“Additionally, vascular cell adhesion molecule 1 (VCAM1) and acid sphingomyelinase (ASM) play a curcial role in destroying the cerebrovascular system,393,394 while cyclophilin A (CyPA) decreases the levels of synapse-related proteins such as the NMDAR subunit NR2B and synaptophysin.395”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [393]
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- Authors
- Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Körbelin, J., Schwaninger, M., Buckwalter, M. S., Quake, S. R., Butcher, E. C., & Wyss-Coray, T.
- Affiliations
- VA Palo Alto Health Care System (US)
- Stanford University (US)
- Stanford Medicine (US)
- Palo Alto Veterans Institute for Research (US)
- University Medical Center Hamburg-Eppendorf (DE)
- University of Lübeck (DE)
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-05-13
- Volume
- 25
- Issue
- 6
- Pages
- 988-1000
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6642642
- OpenAlex
- W2945711076
- Cited by
- 442
- References
- 82
- Citations by year
- 2026: 54 · 2025: 67 · 2024: 62 · 2023: 61 · 2022: 84 · 2021: 49 · 2020: 47 · 2019: 17 · 2018: 1
- FWCI
- 22.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR001085, UL1TR003142)
- National Institute on Aging (F32AG051330, R01AG045034, DP1AG053015)
- National Institute of General Medical Sciences (R01GM037734, T32GM120007)
- National Institute of Allergy and Infectious Diseases (R37AI047822, R01AI109452)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- brain aging, hippocampus, neural progenitor cells, microglial activation, brain endothelial cells, VCAM-1, blood-brain barrier, cognitive impairment, age-related neurodegeneration
- MeSH terms
- Adolescent, Adult, Aged, Aging, Animals, Blood-Brain Barrier, Brain, Cells, Cultured, Female, Hippocampus, Humans, Male, Mice, SCID, Mice, Inbred NOD, Gene Deletion, Microglia, Mice, Knockout, Inflammation Mediators, Vascular Cell Adhesion Molecule-1, Endothelial Cells, Mice, Young Adult, Neural Stem Cells
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