TY  - JOUR
AU  - İş, Özkan
AU  - Wang, Xue
AU  - Reddy, Joseph S
AU  - Min, Yuhao
AU  - Yilmaz, Elanur
AU  - Bhattarai, Prabesh
AU  - Patel, Tulsi
AU  - Bergman, Jeremiah
AU  - Quicksall, Zachary
AU  - Heckman, Michael G
AU  - Tutor-New, Frederick Q
AU  - Can Demirdogen, Birsen
AU  - White, Launia
AU  - Koga, Shunsuke
AU  - Krause, Vincent
AU  - Inoue, Yasuteru
AU  - Kanekiyo, Takahisa
AU  - Cosacak, Mehmet Ilyas
AU  - Nelson, Nastasia
AU  - Lee, Annie J
AU  - Vardarajan, Badri
AU  - Mayeux, Richard
AU  - Kouri, Naomi
AU  - Deniz, Kaancan
AU  - Carnwath, Troy
AU  - Oatman, Stephanie R
AU  - Lewis-Tuffin, Laura J
AU  - Nguyen, Thuy
AU  - Carrasquillo, Minerva M
AU  - Graff-Radford, Jonathan
AU  - Petersen, Ronald C
AU  - Jr Jack, Clifford R
AU  - Kantarci, Kejal
AU  - Murray, Melissa E
AU  - Nho, Kwangsik
AU  - Saykin, Andrew J
AU  - Dickson, Dennis W
AU  - Kizil, Caghan
AU  - Allen, Mariet
AU  - Ertekin-Taner, Nilüfer
TI  - Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2024-00797
SP  - 4758
PY  - 2024
AB  - 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.
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Humans
KW  - Blood-Brain Barrier: metabolism
KW  - Blood-Brain Barrier: pathology
KW  - Smad3 Protein: metabolism
KW  - Smad3 Protein: genetics
KW  - Zebrafish
KW  - Astrocytes: metabolism
KW  - Vascular Endothelial Growth Factor A: metabolism
KW  - Vascular Endothelial Growth Factor A: genetics
KW  - Animals
KW  - Pericytes: metabolism
KW  - Pericytes: pathology
KW  - Male
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Female
KW  - Aged
KW  - Transcriptome
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Brain: blood supply
KW  - Aged, 80 and over
KW  - Disease Models, Animal
KW  - Smad3 Protein (NLM Chemicals)
KW  - Vascular Endothelial Growth Factor A (NLM Chemicals)
KW  - SMAD3 protein, human (NLM Chemicals)
KW  - VEGFA protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11190273
C6  - pmid:38902234
DO  - DOI:10.1038/s41467-024-48926-6
UR  - https://pub.dzne.de/record/270417
ER  -