Enhanced delivery of low-dose of aducanumab via FUS in 5xFAD mice, an AD model

Abstract BackgroundAducanumab (Adu), which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid (Aβ), has been reported to reduce amyloid pathology and improve impaired cognition after the administration of a high dose (10 mg/kg) of the drug in Alzheimer’s disease (AD) clinical trials. The purpose of this study is to investigate the effects of a lower dose of Adu (3mg/kg) with enhanced delivery via focused ultrasound (FUS) in an AD mouse model.MethodsThe FUS with microbubbles opened the blood-brain barrier of the hippocampus for the delivery of Aducanumab. Combined therapy of FUS and Aducanumab was performed three times in total and each treatment was performed biweekly. Y-maze test, Brdu labeling, immunohistochemical experimental methods were employed in this study. In addition, RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.ResultsThe combined treatment with FUS markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains. The combined treatment significantly restored cognitive impairment and decreased the level of amyloid plaques in the hippocampi of 5xFAD mice compared with Adu or FUS alone. The combined treatment with FUS and Adu increased reactive microglia and astrocytes associated with amyloid plaques in the hippocampi of 5xFAD mice. Furthermore, RNA sequencing identified 4 enriched canonical pathways such as phagosome formation, neuroinflammation signaling, CREB signaling and reelin signaling was altered in the hippocami of 5xFAD given the combined treatment. ConclusionIn conclusion, the enhanced delivery of a low dose of Aducanumab via FUS decreased amyloid deposits and restored cognitive function. This study provides better insight into establishing a solid therapeutic strategy for the treatment of AD as well as other neurodegenerative diseases.