e-Article
Gliovascular transcriptional perturbations in Alzheimer’s disease reveal molecular mechanisms of blood brain barrier dysfunction
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-23 (2024)
Subject
Language
English
ISSN
2041-1723
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.