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Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction

Author

Listed:
  • Özkan İş

    (Mayo Clinic)

  • Xue Wang

    (Mayo Clinic)

  • Joseph S. Reddy

    (Mayo Clinic)

  • Yuhao Min

    (Mayo Clinic)

  • Elanur Yilmaz

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Prabesh Bhattarai

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Tulsi Patel

    (Mayo Clinic)

  • Jeremiah Bergman

    (Mayo Clinic)

  • Zachary Quicksall

    (Mayo Clinic)

  • Michael G. Heckman

    (Mayo Clinic)

  • Frederick Q. Tutor-New

    (Mayo Clinic)

  • Birsen Can Demirdogen

    (Mayo Clinic
    TOBB University of Economics and Technology)

  • Launia White

    (Mayo Clinic)

  • Shunsuke Koga

    (Mayo Clinic)

  • Vincent Krause

    (Mayo Clinic)

  • Yasuteru Inoue

    (Mayo Clinic)

  • Takahisa Kanekiyo

    (Mayo Clinic)

  • Mehmet Ilyas Cosacak

    (German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association)

  • Nastasia Nelson

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • Annie J. Lee

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center
    Columbia University)

  • Badri Vardarajan

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center
    Columbia University)

  • Richard Mayeux

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center
    Columbia University
    Columbia University Irving Medical Center)

  • Naomi Kouri

    (Mayo Clinic)

  • Kaancan Deniz

    (Mayo Clinic)

  • Troy Carnwath

    (Mayo Clinic)

  • Stephanie R. Oatman

    (Mayo Clinic)

  • Laura J. Lewis-Tuffin

    (Mayo Clinic)

  • Thuy Nguyen

    (Mayo Clinic)

  • Minerva M. Carrasquillo

    (Mayo Clinic)

  • Jonathan Graff-Radford

    (Mayo Clinic)

  • Ronald C. Petersen

    (Mayo Clinic
    Mayo Clinic Alzheimer’s Disease Research Center)

  • Clifford R. Jack

    (Radiology)

  • Kejal Kantarci

    (Mayo Clinic Alzheimer’s Disease Research Center)

  • Melissa E. Murray

    (Mayo Clinic)

  • Kwangsik Nho

    (Indiana University School of Medicine
    Indiana University School of Medicine
    Indiana University School of Medicine)

  • Andrew J. Saykin

    (Indiana University School of Medicine
    Indiana University School of Medicine
    Indiana University School of Medicine)

  • Dennis W. Dickson

    (Mayo Clinic)

  • Caghan Kizil

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center
    Columbia University)

  • Mariet Allen

    (Mayo Clinic)

  • Nilüfer Ertekin-Taner

    (Mayo Clinic
    Mayo Clinic)

Abstract

To uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer’s disease, we performed single nucleus RNA sequencing in 24 Alzheimer’s disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer’s disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer’s disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer’s disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer’s disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer’s disease.

Suggested Citation

  • Özkan İş & Xue Wang & Joseph S. Reddy & Yuhao Min & Elanur Yilmaz & Prabesh Bhattarai & Tulsi Patel & Jeremiah Bergman & Zachary Quicksall & Michael G. Heckman & Frederick Q. Tutor-New & Birsen Can De, 2024. "Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48926-6
    DOI: 10.1038/s41467-024-48926-6
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