TREM2 TRANSGENIC MODELS PROVIDE INSIGHT INTO POTENTIAL STRATEGIES FOR RESCUING LOSS OF FUNCTION IN ALZHEIMER'S DISEASE

Abstract

TREM2 is an orphan immune receptor expressed on the surface of myeloid cells including macrophages and microglia. Variants in the TREM2 gene, most notably, an Arg to His variant on the extracellular domain have been linked to increased risk for late-onset Alzheimer's disease. While the variant has been shown to have reduced ligand binding and putative compromised microglial barrier function, a strategy to rescue relevant myeloid function in disease remain poorly understood. Here we report the development of transgenic TREM2 mice using a targeted gene-editing based approach. We note a gene dosage dependent survival defect in TREM2R47H myeloid cells (similar to TREM2-/- macrophages and microglia) and perform RNAseq studies to elucidate the effect of the variant on several cellular pathways. We demonstrate that TREM2 agonist antibodies modulate affected pathways and hence may have a beneficial effect in disease.