Single Nuclei Transcriptome Reveals Perturbed Brain Vascular Molecules in Alzheimer's Disease
Blood-brain barrier (BBB) dysfunction is well-known in Alzheimer's disease (AD), but the precise molecular changes contributing to its pathophysiology are unclear. To understand the transcriptional changes in brain vascular cells, we performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains resulting in 79,751 nuclei, 4,604 of which formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge-based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the gliovascular unit (GVU) of the BBB. Vascular targets predicted to interact with astrocytic ligands have biological functions in signaling, angiogenesis, amyloid β metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. Our findings provide information on transcriptional changes in predicted vascular-astrocytic partners at the GVU, bringing insights to the molecular mechanisms of BBB breakdown in AD.