LAUSR

Significance Immunotherapy has been proposed for neurodegenerative disorders including Alzheimer’s disease. Recent reports using antibodies against poly-GA or active immunization suggested similar immunotherapy in ALS/FTD caused by repeat expansion in the C9orf72 gene. Here, we systematically characterized human antibodies against multiple DPR species and tested the biological effects of antibodies targeting poly-GA in different cellular and mouse models. Target engagement was shown in three independent cellular models. Anti-GA antibodies reduced the number of intracellular poly-GA aggregates in human T98G cells but not in cultured human neurons. Chronic anti-GA treatment in BAC C9orf72450 mice did not impact poly-GA levels and modestly improved one behavioral phenotype, whereas poly-GA levels detected by immunoassays were increased and disease progression was unaltered in AAV-(G4C2)149 mice.