Comprehensive analyses of brain cell communications based on multiple scRNA‐seq and snRNA‐seq datasets for revealing novel mechanism in neurodegenerative diseases

Abstract Aims Complex cellular communications between glial cells and neurons are critical for brain normal function and disorders, and single‐cell level RNA‐sequencing datasets display more advantages for analyzing cell communications. Therefore, it is necessary to systematically explore brain cell communications when considering factors such as sex and brain region. Methods We extracted a total of 1,039,459 cells derived from 28 brain single‐cell RNA‐sequencing (scRNA‐seq) or single‐nucleus RNA‐sequencing (snRNA‐seq) datasets from the GEO database, including 12 human and 16 mouse datasets. These datasets were further divided into 71 new sub‐datasets when considering disease, sex, and region conditions. In the meanwhile, we integrated four methods to evaluate ligand–receptor interaction score among six major brain cell types (microglia, neuron, astrocyte, oligodendrocyte, OPC, and endothelial cell). Results For Alzheimer's disease (AD), disease‐specific ligand–receptor pairs when compared with normal sub‐datasets, such as SEMA4A‐NRP1, were identified. Furthermore, we explored the sex‐ and region‐specific cell communications and identified that WNT5A‐ROR1 among microglia cells displayed close communications in male, and SPP1‐ITGAV displayed close communications in the meninges region from microglia to neurons. Furthermore, based on the AD‐specific cell communications, we constructed a model for AD early prediction and confirmed the predictive performance using multiple independent datasets. Finally, we developed an online platform for researchers to explore brain condition‐specific cell communications. Conclusion This research provided a comprehensive study to explore brain cell communications, which could reveal novel biological mechanisms involved in normal brain function and neurodegenerative diseases such as AD.