Gliovascular molecular alterations in Alzheimer’s disease: a cross‐tissue, cross‐species study
Authors: Is Ozkan , Wang Xue , Reddy Joseph S. , Patel Tulsi , Min Yuhao , Quicksall Zachary , Heckman Michael G. , Gao Junli , Bergman Jeremiah , Da Mesquita Sandro Gabriel (Sandro Da Mesquita) Ferreira , Kizil Caghan , Bhattarai Prabesh , Cosacak Mehmet I. , Lee Annie J , Vardarajan Badri N , Mayeux Richard , Koga Shunsuke , Kanekiyo Takahisa , White Launia J , Kouri Naomi , Deniz Kaancan , Tutor‐New Frederick Q , Carnwath Troy , Oatman Stephanie R , Lewis‐Tuffin Laura , Nguyen Thuy , Carrasquillo Minerva M. , Radford Jonathan Graff , Petersen Ronald C. , Jack Clifford R. , Kantarci Kejal , Nho Kwangsik , Saykin Andrew J. , Dickson Dennis W. , Murray Melissa E. , Allen Mariet , Ertekin‐Taner Nilufer 
Published: December 2023

Background

Inter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, and maintenance of the blood‐brain‐barrier (BBB) properties. The breakdown of BBB in Alzheimer’s disease (AD) is well‐established, but precise underlying molecular changes remain unclear. Additionally, whether GVU molecular alterations observed in AD brains are also detected in blood from living patients is unknown. Further, these GVU molecular perturbations require further investigation in different model systems to identify both human brain‐specific and cross‐species conserved alterations. In this study, we investigated prioritized GVU molecules altered in AD brains for their conservation in blood and cross‐species model systems.

Methods

We performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in AD and control brains. We analyzed this data to detect cell‐specific GVU molecular perturbations and their interactions. We investigated molecular interactions between vascular and astrocyte clusters, the major cell types of the GVU of the BBB. To determine whether GVU transcriptional alterations detected in the brain are preserved in the blood, existing blood expression, genetic, and neuroimaging data from two longitudinal antemortem cohorts were analyzed. Using model systems, including mouse, drosophila, and zebrafish, we evaluated the cross‐species conservation of the top GVU alterations detected in AD brains.

Results

Brain snRNAseq revealed transcriptional profiles of 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as pericytes, endothelia and perivascular fibroblasts. We identified differentially expressed genes and their enriched pathways within these clusters and observed the highest levels of transcriptional changes within pericytes. Vascular targets that interact with astrocytic ligands have biological functions in cell signaling, angiogenesis, amyloid ß metabolism, and cytoskeletal architecture. We discovered that genetic variants influencing blood expression levels of some of the prioritized GVU genes were associated with neuroimaging burden of cerebrovascular disease in living human cohorts. Our ongoing studies in model systems revealed conservation of some of the top prioritized molecular perturbations across species.

Conclusion

Our findings prioritized by multiscale, cross‐tissue human data revealed GVU perturbations within interacting pericyte and astrocyte molecules, which are conserved across multiple cross‐species models. These results nominate new molecular targets and mechanistic insights for BBB disruptions in AD.