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

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

doi:10.1186/s40035-022-00333-x

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

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

Department of Neurosurgery

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Article number	57
Journal	Translational Neurodegeneration
Volume	11
Issue number	1
DOIs	https://doi.org/10.1186/s40035-022-00333-x
Publication status	Published - 2022 Dec

Bibliographical note

Funding Information:
We would like to thank professor Young Cheol Na for comments. And also, we thank the Bioinformatics Collaboration Unit, Yonsei University College of Medicine for the RNA sequencing analysis support.

Funding Information:
This study was financially supported by grants from 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) and 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.

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

Clinical Neurology
Cognitive Neuroscience
Cellular and Molecular Neuroscience

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s40035-022-00333-x

Cite this

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

abstract = "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{\textquoteright}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.",

author = "Chanho Kong and Yang, {Eun Jeong} and Jaewoo Shin and Junwon Park and Kim, {Si Hyun} and Park, {Seong Wook} and Chang, {Won Seok} and Lee, {Chang Han} and Hyunju Kim and Kim, {Hye Sun} and Chang, {Jin Woo}",

note = "Funding Information: We would like to thank professor Young Cheol Na for comments. And also, we thank the Bioinformatics Collaboration Unit, Yonsei University College of Medicine for the RNA sequencing analysis support. Funding Information: This study was financially supported by grants from 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) and 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. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s40035-022-00333-x",

language = "English",

volume = "11",

journal = "Translational Neurodegeneration",

issn = "2047-9158",

publisher = "BioMed Central",

number = "1",

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T1 - Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model

AU - Kong, Chanho

AU - Yang, Eun Jeong

AU - Shin, Jaewoo

AU - Park, Junwon

AU - Kim, Si Hyun

AU - Park, Seong Wook

AU - Chang, Won Seok

AU - Lee, Chang Han

AU - Kim, Hyunju

AU - Kim, Hye Sun

AU - Chang, Jin Woo

N1 - Funding Information: We would like to thank professor Young Cheol Na for comments. And also, we thank the Bioinformatics Collaboration Unit, Yonsei University College of Medicine for the RNA sequencing analysis support. Funding Information: This study was financially supported by grants from 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) and 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. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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UN SDGs

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