Nature Communications (Jun 2024)
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,
- for the Alzheimer’s Disease Neuroimaging Initiative,
- Minerva M. Carrasquillo,
- Jonathan Graff-Radford,
- Ronald C. Petersen,
- Clifford R. Jr Jack,
- Kejal Kantarci,
- Melissa E. Murray,
- Kwangsik Nho,
- Andrew J. Saykin,
- Dennis W. Dickson,
- Caghan Kizil,
- Mariet Allen,
- Nilüfer Ertekin-Taner
Affiliations
- Özkan İş
- Department of Neuroscience, Mayo Clinic
- Xue Wang
- Department of Quantitative Health Sciences, Mayo Clinic
- Joseph S. Reddy
- Department of Quantitative Health Sciences, Mayo Clinic
- Yuhao Min
- Department of Neuroscience, Mayo Clinic
- Elanur Yilmaz
- Department of Neurology, Columbia University Irving Medical Center
- Prabesh Bhattarai
- Department of Neurology, Columbia University Irving Medical Center
- Tulsi Patel
- Department of Neuroscience, Mayo Clinic
- Jeremiah Bergman
- Department of Neuroscience, Mayo Clinic
- Zachary Quicksall
- Department of Quantitative Health Sciences, Mayo Clinic
- Michael G. Heckman
- Department of Quantitative Health Sciences, Mayo Clinic
- Frederick Q. Tutor-New
- Department of Neuroscience, Mayo Clinic
- Birsen Can Demirdogen
- Department of Neuroscience, Mayo Clinic
- Launia White
- Department of Quantitative Health Sciences, Mayo Clinic
- Shunsuke Koga
- Department of Neuroscience, Mayo Clinic
- Vincent Krause
- Department of Neuroscience, Mayo Clinic
- Yasuteru Inoue
- Department of Neuroscience, Mayo Clinic
- Takahisa Kanekiyo
- Department of Neuroscience, Mayo Clinic
- Mehmet Ilyas Cosacak
- German Center for Neurodegenerative Diseases (DZNE) within Helmholtz Association
- Nastasia Nelson
- Department of Neurology, Columbia University Irving Medical Center
- Annie J. Lee
- Department of Neurology, Columbia University Irving Medical Center
- Badri Vardarajan
- Department of Neurology, Columbia University Irving Medical Center
- Richard Mayeux
- Department of Neurology, Columbia University Irving Medical Center
- Naomi Kouri
- Department of Neuroscience, Mayo Clinic
- Kaancan Deniz
- Department of Neuroscience, Mayo Clinic
- Troy Carnwath
- Department of Neuroscience, Mayo Clinic
- Stephanie R. Oatman
- Department of Neuroscience, Mayo Clinic
- Laura J. Lewis-Tuffin
- Mayo Clinic Florida Cytometry and Cell Imaging Laboratory, Mayo Clinic
- Thuy Nguyen
- Department of Neuroscience, Mayo Clinic
- for the Alzheimer’s Disease Neuroimaging Initiative
- Minerva M. Carrasquillo
- Department of Neuroscience, Mayo Clinic
- Jonathan Graff-Radford
- Department of Neurology, Mayo Clinic
- Ronald C. Petersen
- Department of Neurology, Mayo Clinic
- Clifford R. Jr Jack
- Mayo Clinic, Radiology
- Kejal Kantarci
- Mayo Clinic Alzheimer’s Disease Research Center
- Melissa E. Murray
- Department of Neuroscience, Mayo Clinic
- Kwangsik Nho
- Center for Computational Biology and Bioinformatics, Indiana University School of Medicine
- Andrew J. Saykin
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic
- Caghan Kizil
- Department of Neurology, Columbia University Irving Medical Center
- Mariet Allen
- Department of Neuroscience, Mayo Clinic
- Nilüfer Ertekin-Taner
- Department of Neuroscience, Mayo Clinic
- DOI
- https://doi.org/10.1038/s41467-024-48926-6
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
