Integration of unpaired transcriptome and epigenome data of mouse whole brain and computational analysis for finding clues of aging

Abstract

Aging is associated with changes in cellular composition and signaling pathways in the brain, leading to an increased risk of neurodegenerative diseases. While the risk factors of specific aged cell types or the changes in the specific brain regions related to disease are well-studied, little is known about the intrinsic features of whole mouse brain aging. We performed single-nucleus RNA sequencing (snRNA-seq), single-cell RNA sequencing (scRNA-seq), and single-nucleus ATAC sequencing (snATAC-seq) and integrated an unpaired multiomics dataset to explore the transcriptional and epigenomic alterations in the aged mouse brain. Focusing on alterations within cell types, we uncovered age-related populations, such as age-related microglia (Micro-3), age-related capillary endothelial cells (Endo-C2), and Meis2 high-expression GABAergic neurons. Our findings also revealed significant shifts in intracellular interaction and signaling pathways, including GRN (Granulin) and RELN (Reelin), which show increased neuronal involvement in the aged brain. Notably, Meis2 high GABAergic neurons and ENDO-C2 endothelial cells exhibit prominent alterations in signal reception and transmission, correlating with upregulated inflammatory markers and compromised vascular integrity. All of these changes highlight the critical roles of inflammatory microglia and signaling between neurons and endothelial cells in aging-related neurodegeneration, providing potential markers of cognitive decline and brain diseases.