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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