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 Yılmaz, Prabesh Bhattarai, Tulsi Patel, Jeremiah Bergman, Zachary Quicksall, Michael G. Heckman, Frederick Q Tutor‐New, Birsen Can Demirdöğen, Launia J. White, Shunsuke Koga, Vincent Krause, Yasuteru Inoue, Takahisa Kanekiyo, Mehmet İlyas Coşacak, Nastasia Nelson, Annie Lee, Badri N. 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. Jack, Kejal Kantarci, Melissa E. Murray, Kwangsik Nho, Andrew J. Saykin, Dennis W. Dickson, Çağhan Kızıl, Mariet Allen, Nilüfer Ertekin‐Taner
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.