Journal Article

DZNE-2024-00797

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.

İş, Ö. ; Wang, X. ; Reddy, J. S. ; Min, Y. ; Yilmaz, E. ; Bhattarai, P.Extern* ; Patel, T. ; Bergman, J. ; Quicksall, Z. ; Heckman, M. G. ; Tutor-New, F. Q. ; Can Demirdogen, B. ; White, L. ; Koga, S. ; Krause, V. ; Inoue, Y. ; Kanekiyo, T. ; Cosacak, M. I.DZNE* ; Nelson, N. ; Lee, A. J. ; Vardarajan, B. ; Mayeux, R. ; Kouri, N. ; Deniz, K. ; Carnwath, T. ; Oatman, S. R. ; Lewis-Tuffin, L. J. ; Nguyen, T. ; Initiative, A. D. N. (Collaboration Author) ; Carrasquillo, M. M. ; Graff-Radford, J. ; Petersen, R. C. ; Jr Jack, C. R. ; Kantarci, K. ; Murray, M. E. ; Nho, K. ; Saykin, A. J. ; Dickson, D. W. ; Kizil, C.Extern* ; Allen, M. ; Ertekin-Taner, N.

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-024-48926-6

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.

Keyword(s): Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Humans (MeSH) ; Blood-Brain Barrier: metabolism (MeSH) ; Blood-Brain Barrier: pathology (MeSH) ; Smad3 Protein: metabolism (MeSH) ; Smad3 Protein: genetics (MeSH) ; Zebrafish (MeSH) ; Astrocytes: metabolism (MeSH) ; Vascular Endothelial Growth Factor A: metabolism (MeSH) ; Vascular Endothelial Growth Factor A: genetics (MeSH) ; Animals (MeSH) ; Pericytes: metabolism (MeSH) ; Pericytes: pathology (MeSH) ; Male (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Transcriptome (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Brain: blood supply (MeSH) ; Aged, 80 and over (MeSH) ; Disease Models, Animal (MeSH) ; Smad3 Protein ; Vascular Endothelial Growth Factor A ; SMAD3 protein, human ; VEGFA protein, human

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Contributing Institute(s):

1. Mechanisms of Induced Plasticity of the Vertebrate Brain (AG Kizil)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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