PUBLICATION
Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction
- Authors
- İş, Ö., Wang, X., Reddy, J.S., Min, Y., Yilmaz, E., Bhattarai, P., 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., Nelson, N., Lee, A.J., Vardarajan, B., Mayeux, R., Kouri, N., Deniz, K., Carnwath, T., Oatman, S.R., Lewis-Tuffin, L.J., Nguyen, T., Alzheimer’s Disease Neuroimaging Initiative, 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., Allen, M., Ertekin-Taner, N.
- ID
- ZDB-PUB-240621-11
- Date
- 2024
- Source
- Nature communications 15: 47584758 (Journal)
- Registered Authors
- Bhattarai, Prabesh, Cosacak, Mehmet Ilyas, Kizil, Caghan, Yilmaz, Elanur
- Keywords
- none
- Datasets
- GEO:GSE225721
- MeSH Terms
-
- Blood-Brain Barrier*/metabolism
- Blood-Brain Barrier*/pathology
- Female
- Animals
- Induced Pluripotent Stem Cells/metabolism
- Astrocytes*/metabolism
- Transcriptome
- Zebrafish*
- Vascular Endothelial Growth Factor A*/genetics
- Vascular Endothelial Growth Factor A*/metabolism
- Humans
- Aged
- Smad3 Protein*/genetics
- Smad3 Protein*/metabolism
- Disease Models, Animal
- Male
- Aged, 80 and over
- Alzheimer Disease*/genetics
- Alzheimer Disease*/metabolism
- Alzheimer Disease*/pathology
- Pericytes*/metabolism
- Pericytes*/pathology
- Brain/blood supply
- Brain/metabolism
- Brain/pathology
- PubMed
- 38902234 Full text @ Nat. Commun.
Citation
İş, Ö., Wang, X., Reddy, J.S., Min, Y., Yilmaz, E., Bhattarai, P., 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., Nelson, N., Lee, A.J., Vardarajan, B., Mayeux, R., Kouri, N., Deniz, K., Carnwath, T., Oatman, S.R., Lewis-Tuffin, L.J., Nguyen, T., Alzheimer’s Disease Neuroimaging Initiative, 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., Allen, M., Ertekin-Taner, N. (2024) Gliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction. Nature communications. 15:47584758.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping