Browsing by Author "İş, Özkan"

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    Cell-specific transcriptional signatures of vascular cells in Alzheimer’s disease: perspectives, pathways, and therapeutic directions
    (Springer Nature, 2025-01-29) Chaudhuri, Soumilee; Cho, Minyoung; Stumpff, Julia C.; Bice, Paula J; İş, Özkan; Ertekin-Taner, Nilüfer; Saykin, Andrew J.; Nho, Kwangsik
    Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is marked by profound neurovascular dysfunction and significant cell-specific alterations in the brain vasculature. Recent advances in high throughput single-cell transcriptomics technology have enabled the study of the human brain vasculature at an unprecedented depth. Additionally, the understudied niche of cerebrovascular cells, such as endothelial and mural cells, and their subtypes have been scrutinized for understanding cellular and transcriptional heterogeneity in AD. Here, we provide an overview of rich transcriptional signatures derived from recent single-cell and single-nucleus transcriptomic studies of human brain vascular cells and their implications for targeted therapy for AD. We conducted an in-depth literature search using Medline and Covidence to identify pertinent AD studies that utilized single-cell technologies in human post-mortem brain tissue by focusing on understanding the transcriptional differences in cerebrovascular cell types and subtypes in AD and cognitively normal older adults. We also discuss impaired cellular crosstalk between vascular cells and neuroglial units, as well as astrocytes in AD. Additionally, we contextualize the findings from single-cell studies of distinct endothelial cells, smooth muscle cells, fibroblasts, and pericytes in the human AD brain and highlight pathways for potential therapeutic interventions as a concerted multi-omic effort with spatial transcriptomics technology, neuroimaging, and neuropathology. Overall, we provide a detailed account of the vascular cell-specific transcriptional signatures in AD and their crucial cellular crosstalk with the neuroglial unit.
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    Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction
    (Springer Nature, 2024-06-20) İş, Özkan; Wang, Xue; Reddy, Joseph S.; Min, Yuhao; Yilmaz, Elanur; Bhattarai, Prabesh; Patel, Tulsi; Bergman, Jeremiah; Quicksall, Zachary; Heckman, Michael G.; Tutor-New, Frederick Q.; Demirdogen, Birsen Can; White, Launia; Koga, Shunsuke; Krause, Vincent; Inoue, Yasuteru; Kanekiyo, Takahisa; Cosacak, Mehmet Ilyas; Nelson, Nastasia; Lee, Annie J.; Vardarajan, Badri; Mayeux, Richard; Kouri, Naomi; Deniz, Kaancan; Carnwath, Troy; Oatman, Stephanie R.; Lewis-Tuffin, Laura J.; Nguyen, Thuy; Alzheimer’s Disease Neuroimaging Initiative; Carrasquillo, Minerva M.; Graff-Radford, Jonathan; Petersen, Ronald C.; Jack, Clifford R., Jr.; Kantarci, Kejal; Murray, Melissa E.; Nho, Kwangsik; Saykin, Andrew J.; Dickson, Dennis W.; Kizil, Caghan; Allen, Mariet; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    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.