Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells.

Overview

1. Division of Microbiology, Tulane National Biomedical Research Center, Tulane University, Covington, Louisiana, USA
2. Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, USA
3. Division of Comparative Pathology, Tulane National Biomedical Research Center, Tulane University, Covington, Louisiana, USA
4. Center for Biomedical Informatics & Genomics, John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
5. Department of Neuroscience and CRCHUM, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
6. Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA

Abstract

Blood–brain barrier (BBB) integrity naturally declines with age. Brain endothelial cells (ECs) and pericytes (PCs) form the BBB, and aging impairs tight junctions, likely via altered PC-to-EC signaling. However, the molecular mechanisms underlying this impairment remain unclear. Using single-cell RNA sequencing, we profiled 68,316 brain ECs expressing 15,564 genes from young and old mice. Unsupervised clustering and annotation revealed five distinct EC subtypes—Capillary EC1, Capillary EC2, Arterial EC, Venous EC1, and Venous EC2—defined by marker genes Mfsd2a, Plvap, Bmx, Nr2f2, and Vcam1, respectively. Aging shifted EC subtype distribution, with reduced Capillary EC1 (45% vs. 57%) and increased Arterial (33% vs. 16%) and Venous ECs (12% vs. 2%) compared with young mice. Mio analysis further showed that Capillary EC1 and Venous EC2 neighborhoods were less abundant in aged brains. Biotin metabolism was decreased in old vs. young mice, particularly within Capillary EC1, Capillary EC2, and Arterial EC. Although widespread gene downregulation was observed across EC subsets, overall expression trends were largely consistent among clusters. Key genes—Ramp2, Hbb-bs, Ly6c1, Calm1—were less abundant, whereas Rasgrf2 was uniquely enriched in aged mice. Immunohistochemistry confirmed reduced LY6C and RAMP2 and elevated RASGRF2 in aged mouse and human brains. Cell–cell interaction analyses revealed age-associated remodeling of ligand-receptor signaling. Enrichment analyses implicated pathways involved in neurovascular integrity, inflammation, amyloid processing, and vascular remodeling. Collectively, these findings show that aging reprograms EC subtype composition, gene expression, and metabolism, thereby contributing to BBB disruption and neurovascular dysfunction.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE147693, at NCBI GEO; found in the text, “Gene–gene interaction and cross-study…”

Data availability

Data will be available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 7 authors, 6 keywords, 2 funders, 106 references, 1 RRID.

Cite

This paper

Nguyen, H. D., Siddiqui, S., Bohannon, D. G., Blair, R. V., Deng, H.-W., Prat, A., & Kim, W.-K. (2026). Single-cell transcriptomic analysis reveals age-related remodeling of brain endothelial cells. Aging brain, 10, 100164. https://doi.org/10.1016/j.nbas.2026.100164

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