BioRxiv

Spatial profiling of chromatin accessibility reveals alteration of glial cells in Alzheimer’s disease mouse brain

Dehui Kong, Hongjie He, Joseph Lechner, Jing Yang, Aijun Zhang, Ling Li, Ramkumar Mathur, Diane C. Darland, Motoki Takaku, Lu Lu, Junmin Peng, Kai Yang, Xusheng Wang

Abstract

Abnormal epigenetic modifications, including altered chromatin accessibility, have been implicated in the development and progression of Alzheimer’s disease (AD). In this study, we applied spatially resolved chromatin accessibility profiling by performing spatial assay for transposase-accessible chromatin using sequencing (ATAC-seq) to analyze brain tissues from 5×FAD AD model and C57BL/6J control mice. Our analysis identified seven major cell types across 11 brain regions and further characterized glial subtypes—microglia and astrocytes—revealing subtype-specific chromatin accessibility changes in 5×FAD mice relative to controls. These alterations were associated with AD-related pathways, including neuroinflammation and immune dysregulation, and synaptic dysfunction and neuronal signaling in microglia, as well as lysosomal and proteasomal activity, lipoprotein metabolism, and mitochondrial dysfunction in astrocytes. We also characterized cell-type-specific enrichments of motifs and transcription factors, including enrichment of Bcl11a in microglia. Furthermore, we linked chromatin accessibility changes in 5×FAD mice to human AD risk genes, highlighting altered epigenetic signatures in genes such as Trem2. Supporting the spatial ATAC-seq findings, flow cytometry validated a selective increase in VISTA (encoded by Vsir) protein expression in 5×FAD microglia, supporting the spatial ATAC-seq findings and indicating a shift toward a pro-inflammatory, disease-associated microglial (DAM-like) phenotype. These findings underscore the utility of spatial chromatin accessibility profiling for uncovering brain-region specific cell identities and epigenetic mechanisms underlying AD pathogenesis.