Spatial ATAC-seq Unmasks Early Glial Rewiring in Alzheimer’s
Region-resolved chromatin maps reveal inflammatory priming across hippocampus and cortex
Author: Atlasxomics Team
Introduction
A new preprint from Kong et al. applies AtlasXomics spatial ATAC-seq to sagittal sections of six-month 5×FAD mice—an age when plaques are still sparse—to ask a deceptively simple question: where do glia first abandon homeostasis? By tiling a 25 µm array across the brain they generated 2,253 pixel-level chromatin profiles in 5×FAD and 2,345 in matched controls, each with ~76 k unique fragments (median) and robust TSS enrichment, providing a high-fidelity canvas for epigenome cartography.
Key findings from the spatial ATAC-seq analysis
Region-specific cell-type shifts. Seven major cell classes were resolved; microglia and astrocytes expanded significantly in 5×FAD, concentrating around the hippocampal CA1–CA3 axis and dentate gyrus.
Early inflammatory programming. Microglia split into four states—homeostatic, pro-inflammatory, anti-inflammatory and disease-associated (DAM). DAMs were enriched in hippocampus, with heightened accessibility at Apoe, Lpl and other immune/metabolic loci.
Astrocytic metabolic stress. Reactive A1- and A2-like astrocytes gained accessibility at genes linked to lysosomal, lipoprotein and mitochondrial pathways, while ion-buffering loci lost accessibility, hinting at impaired neuronal support.
Transcription-factor re-wiring. Microglial peaks were strongly enriched for PU.1 and, strikingly, BCL11A motifs; BCL11A protein itself was elevated in 5×FAD microglia.
Checkpoint up-regulation. The microglial immune brake Vsir (VISTA) showed both chromatin and protein gains, especially in TREM2⁺ DAM-like cells, suggesting a subtype-specific immunoregulatory loop.
Link to human genetics. Accessibility at several GWAS-nominated AD genes (Trem2, Cd33, Havcr2) rose selectively in microglia, reinforcing their pathogenic relevance.
Why it matters
By anchoring chromatin change to precise coordinates, the study reframes early Alzheimer’s as a regional epigenetic disorder rather than a uniform, late-stage plaque response. The discovery of hippocampal-centric DAM expansion, BCL11A motif gain and VISTA activation offers fresh, spatially validated nodes for therapeutic intervention—targets that bulk or dissociated single-cell assays would dilute or miss.
Technical highlights for AtlasXomics users
Quality first. Pixels with TSS enrichment < 4 were removed, followed by a fixed ≥10 k-fragment filter—simple yet effective for maintaining signal without over-trimming.
Power of “only” 25 µm. Even with a Gen-1 25 µm chip (≈ 5–10cells per pixel), the team captured glia–neuron boundaries and microglia–astrocyte cross-talk; upcoming 10 µm chemistry promises single-cell precision.
Integrated validation. Flow-cytometry confirmation of APOE, BCL11A and VISTA protein changes underscores the reliability of chromatin-based calls.
Open questions
Does microglial chromatin priming drive amyloid build-up, or is it an independent stress response?
Can similar spatial epigenetic signatures be recovered from human FFPE cortex, where fixation lowers yield?
Will dampening BCL11A or VISTA activity in hippocampal microglia alter disease trajectory?
Conclusion
Kong et al. deliver the first pixel-resolved epigenomic map of the 5×FAD brain, revealing glial regulatory shifts that precede overt pathology. For researchers, the message is clear: spatial ATAC-seq is not just a mapping tool—it is an early-warning system for tissue-specific regulatory failure, ready to be sharpened further as resolution advances.
Further reading
Spatial profiling of chromatin accessibility reveals alteration of glial cells in Alzheimer’s disease mouse brain (bioRxiv, posted 7 May 2025).
