Basic Science and Pathogenesis.

Background: Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. We've previously described a high-affinity mouse TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), ATV:4D9. Single-cell RNA sequencing and morphometry revealed that ATV:4D9 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. However, the factors mediating ATV:4D9-induced transcriptional responses in microglia is not known.

Method: We performed fluorescence-activated nuclei sorting (FANS) to isolate PU.1+ microglial nuclei from frozen brain tissue followed by assaying for transposase-accessible chromatin with sequencing (ATAC-Seq) to determine regions of accessible chromatin in the microglial genome.

Result: We identified changes in chromatin accessibility that are observed in microglia dosed with ATV:4D9 compared to isotype control antibody. Bioinformatic analysis identified motifs for putative regulatory transcription factors in ATV:4D9-activated enhancers.

Conclusion: Our data provide insights into putative transcription factors that mediate microglial state changes in response to ATV:4D9, which further elucidates mechanisms of TREM2 agonism.