Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice,an AD model

作     者：Chanho Kong Eun-Jeong Yang Jaewoo Shin Junwon Park Si-Hyun Kim Seong-Wook Park Won Seok Chang Chang-Han Lee Hyunju Kim Hye-Sun Kim Jin Woo Chang 

作者机构：Department of NeurosurgeryYonsei University College of Medicine50 Yonsei-RoSeodaemun-GuSeoulRepublic of Korea Department of PharmacologyCollege of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Neuroscience Research CenterCollege of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Department of Biomedical SciencesCollege of MedicineSeoul National University103 DaehakroJongro-GuSeoulRepublic of Korea Bundang HospitalSeoul National University College of MedicineBundang-GuSungnamRepublic of Korea. 

出 版 物：《Translational Neurodegeneration》 (转化神经变性病（英文）)

年 卷 期：2022年第11卷第1期

页      面：31-45页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100203[医学-老年医学] 10[医学] 

基　　金：the Healthcare Technology R&D Project(HI19C0060)by the Ministry for Health,Welfare,and Family Affairs,Republic of Korea In addition,this work was supported by Seoul National University Bundang Hospital Research Fund,South Korea(14-2021-0004) National Research Foundation of Korea(NRF)grant funded by the Korea government(MIST)(Grant no.2020R1A2C1011839)to HS.Kim.Also,H.Kim and EJ.Yang received a scholarship from the BK21-Plus Education Program provided by the National Research Foundation of Korea. 

主　　题：Aducanumab Alzheimer’s disease Focused ultrasound Transcriptome profiling 

摘      要：Background:Aducanumab(Adu),which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid,has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose(10 mg/kg)of the drug in Alzheimer’s disease(AD)clinical trials.The purpose of this study was to investigate the effects of a lower dose of Adu(3 mg/kg)with enhanced delivery via focused ultrasound(FUS)in an AD mouse model.Methods:The FUS with microbubbles opened the blood-brain barrier(BBB)of the hippocampus for the delivery of Adu.The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly.Y-maze test,Brdu labeling,and 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.Results:The FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains.The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone.Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice.Furthermore,RNA sequencing identified that 4 enriched canonical pathways including phagosome formation,neuroinflammation signaling,CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.Conclusion:In conclusion,the enhanced delivery of a low dose of Adu(3 mg/kg)via FUS decreases amyloid deposits and attenuates cognitive function deficits.FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery.We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.