Cerebrovascular Single-Nucleus RNA-Seq Reveals Heat Shock Activation and Vascular Remodeling in Alzheimer’s Disease and Primary Tauopathies
Year: 2026
Type: preprint
Abstract: Cerebrovascular alterations are widely observed in both Alzheimer’s Disease (AD) and primary tauopathies. Here, we hypothesized that mechanisms of cerebrovascular alterations are shared between AD and primary tauopathies. We performed single-nucleus RNA sequencing of postmortem human inferior temporal gyrus to characterize transcriptomic changes across cerebrovascular cell types in AD and primary tauopathies (Corticobasal Degeneration, Pick’s disease, and Progressive Supranuclear Palsy). Differential gene expression analyses revealed disease-specific transcriptional programs across vascular cell populations. However, genes involved in the heat-shock response were consistently upregulated across all diseases, suggesting a conserved cerebrovascular stress response during neurodegeneration. We further identified marked cerebrovascular remodeling in AD relative to primary tauopathies, along with dysregulation of genes mapping to AD risk loci in endothelial cells. Transcriptomic findings were validated using tissue clearing, light-sheet microscopy, and immunofluorescence quantification of vascular markers. These results define a conserved vascular stress program alongside AD-specific remodeling, highlighting the vasculature as a therapeutic target in neurodegeneration.
Source: Research Square
Authors: L. Daniel Estrella, Swarnali Dasgupta, Akhila Gundavelli, Huan Li, Stanley H. Yang, Sarah Chancellor, Tim Pastika, Aicha Abdourahman, Joseph Tamm, Kiran Yanamandra, Nandani Romanul, Fan Liao, Karen Zhao, Gen Lin, Pooja Srinivasa, Xinge Wang, Annita Martin, Elizabeth Asque, Astrid Doering, Janina S. Ried, Robert V. Talanian, Taekyung Kwon, Maya E. Woodbury, Yelena Y. Grinberg, Ergina Agastra, Derek H. Oakley, Bradley T. Hyman, Alberto Serrano-Pozo, Theodore Zwang, Sudeshna Das, Rachel E. Bennett
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7166465827