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

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 Demirdogen, Launia White, Shunsuke Koga, Vincent Krause, Yasuteru Inoue, Takahisa Kanekiyo, Mehmet Ilyas Cosacak, Nastasia Nelson, Annie J. Lee, Badri Vardarajan, Richard Mayeux, Naomi Kouri, Kaancan Deniz, Troy Carnwath, Stephanie R. Oatman, Laura J. Lewis-Tuffin, Thuy Nguyen, Minerva M. Carrasquillo, Jonathan Graff-Radford, Ronald C. Petersen, Clifford R. Jack, Kejal Kantarci, Melissa E. Murray, Kwangsik Nho, Andrew J. Saykin, Dennis W. Dickson, Caghan Kizil, Mariet Allen and Nilüfer Ertekin-Taner ()
Additional contact information
Özkan İş: Mayo Clinic
Xue Wang: Mayo Clinic
Joseph S. Reddy: Mayo Clinic
Yuhao Min: Mayo Clinic
Elanur Yilmaz: Columbia University Irving Medical Center
Prabesh Bhattarai: 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
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
Annie J. Lee: Columbia University Irving Medical Center
Badri Vardarajan: Columbia University Irving Medical Center
Richard Mayeux: 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
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
Andrew J. Saykin: Indiana University School of Medicine
Dennis W. Dickson: Mayo Clinic
Caghan Kizil: Columbia University Irving Medical Center
Mariet Allen: Mayo Clinic
Nilüfer Ertekin-Taner: Mayo Clinic

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48926-6

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