A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer’s disease and multiple sclerosis

Unlike stalk-binding anti-TREM2 agonist antibodies, 03O05 preserves ectodomain shedding, leading to transient receptor activation and increased sTREM2 levels. This approach promotes a neuroprotective microglial phenotype without inducing neuroinflammation, reduces amyloid pathology and neuronal dystrophy, as well as supports remyelination in multiple sclerosis (MS). These findings suggest the therapeutic potential of shedding-permissive TREM2 agonism in neurodegenerative disease.