NVUAtlas: A Comprehensive Single-Nucleus RNA-Seq Resource for the Human Neurovascular Unit in Alzheimer's Disease

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Neurovascular unit (NVU) dysfunction is an early factor in Alzheimer's disease (AD) pathogenesis.
• Standard single-nucleus RNA sequencing (snRNA-seq) lacks resolution for NVU vascular and mural cells.
• Existing transcriptomic atlases do not capture intercellular signaling in NVU vascular components like endothelial cells and pericytes.

Purpose of the Study:

• To construct a high-resolution transcriptomic atlas of the human NVU.
• To investigate NVU dysfunction at the molecular level, focusing on vascular cells.
• To identify sex-specific differences in NVU molecular mechanisms in AD.

Main Methods:

• Integrated 11 vascular-enriched snRNA-seq datasets from the human prefrontal cortex.
• Utilized deep generative models (SCVI) for batch-aware integration of over 4.2 million nuclei.
• Employed advanced classifiers for cell type re-annotation and performed differential expression and ligand-receptor analyses.

Main Results:

• Assembled the largest public NVU cohort, including endothelial cells and pericytes.
• Observed transcriptional hyperactivity (gene upregulation) in vascular cells in AD, contrasting neuronal downregulation.
• Identified sex-specific vulnerabilities: females showed inflammatory signatures and reduced collagen gene expression in pericytes.

Conclusions:

• The Human NVU Atlas offers a detailed transcriptomic framework for studying NVU cellular heterogeneity.
• Revealed sex-specific vascular mechanisms and disrupted intercellular communication in AD.
• Underscores the importance of vascular cells and extracellular matrix integrity in AD pathogenesis.