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Nature neuroscience
Mar 14, 2025;

Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.

Omar M F Omar, Amy L Kimble, Ashok Cheemala, Jordan D Tyburski, Swati Pandey, Qian Wu, Bo Reese, Evan R Jellison, Bing Hao, Yunfeng Li, Riqiang Yan, Patrick A Murphy
Author Information
  1. Omar M F Omar: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA. ORCID
  2. Amy L Kimble: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA. ORCID
  3. Ashok Cheemala: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA.
  4. Jordan D Tyburski: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA. ORCID
  5. Swati Pandey: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA.
  6. Qian Wu: Department of Pathology, University of Connecticut Medical School, Farmington, CT, USA.
  7. Bo Reese: Center for Genome Innovation, University of Connecticut, Storrs, CT, USA.
  8. Evan R Jellison: Department of Immunology, University of Connecticut Medical School, Farmington, CT, USA. ORCID
  9. Bing Hao: Department of Molecular Biology and Biophysics, University of Connecticut Medical School, Farmington, CT, USA.
  10. Yunfeng Li: Department of Molecular Biology and Biophysics, University of Connecticut Medical School, Farmington, CT, USA.
  11. Riqiang Yan: Department of Neuroscience, University of Connecticut Medical School, Farmington, CT, USA.
  12. Patrick A Murphy: Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA. pamurphy@uchc.edu. ORCID
PMID: 40087396 DOI: 10.1038/s41593-025-01914-5

Abstract

Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear ��-catenin and ��-catenin-downstream genes, along with elevated TNF/NF-��B markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.

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Grants

  1. 19IPLOI34770151/American Heart Association (American Heart Association, Inc.)
  2. 23PRE1027078/American Heart Association (American Heart Association, Inc.)
  3. R00-HL125727/U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
  4. RF1-NS117449/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
  5. NS074256/U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
  6. GM135592/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
  7. AG046929/U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
Journal Article
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