Please use this identifier to cite or link to this item:
https://hdl.handle.net/20.500.11851/11621
Title: | Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction | Authors: | İş, Özkan Wang, Xue Reddy, Joseph S. Min, Yuhao Yılmaz, Elanur Bhattarai, Prabesh Patel, Tulsi |
Keywords: | Endothelial Growth-Factor Cell Hipsc Lines Gene-Expression Angiogenesis Generation Neurodegeneration Biomarkers Dementia Cloning Vegf |
Publisher: | Nature portfolio | 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. Systematic studies are needed to discover molecular determinants of blood brain barrier dysfunction in Alzheimer's disease. This study identifies perturbed pericytic SMAD3-astrocytic VEGFA interactions as a potential driver of this dysfunction. | URI: | https://doi.org/10.1038/s41467-024-48926-6 https://hdl.handle.net/20.500.11851/11621 |
ISSN: | 2041-1723 |
Appears in Collections: | PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection |
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