Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease

Byung Jo Choi, Min Hee Park, Kang Ho Park, Wan Hui Han, Hee Ji Yoon, Hye Yoon Jung, Ju Yeon Hong, Md Riad Chowdhury, Kyung Yeol Kim, Jihoon Lee, Im-Sook Song, Minyeong Pang, Min-Koo Choi, Erich Gulbins, Martin Reichel, Johannes Kornhuber, Chang-Won Hong, Changho Kim, Seung Hyun Kim, Edward H. Schuchman, Hee Kyung Jin () and Jae-sung Bae ()
Additional contact information
Byung Jo Choi: Kyungpook National University
Min Hee Park: Kyungpook National University
Kang Ho Park: Kyungpook National University
Wan Hui Han: Kyungpook National University
Hee Ji Yoon: Kyungpook National University
Hye Yoon Jung: Kyungpook National University
Ju Yeon Hong: Kyungpook National University
Md Riad Chowdhury: Kyungpook National University
Kyung Yeol Kim: Kyungpook National University
Jihoon Lee: Kyungpook National University
Im-Sook Song: Kyungpook National University
Minyeong Pang: Dankook University
Min-Koo Choi: Dankook University
Erich Gulbins: University of Duisburg-Essen
Martin Reichel: Friedrich-Alexander-University of Erlangen-Nuremberg
Johannes Kornhuber: Friedrich-Alexander-University of Erlangen-Nuremberg
Chang-Won Hong: Kyungpook National University
Changho Kim: Kyungpook National University
Seung Hyun Kim: Hanyang University College of Medicine
Edward H. Schuchman: Icahn School of Medicine at Mount Sinai
Hee Kyung Jin: Kyungpook National University
Jae-sung Bae: Kyungpook National University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Acid sphingomyelinase (ASM) has been implicated in neurodegenerative disease pathology, including Alzheimer’s disease (AD). However, the specific role of plasma ASM in promoting these pathologies is poorly understood. Herein, we explore plasma ASM as a circulating factor that accelerates neuropathological features in AD by exposing young APP/PS1 mice to the blood of mice overexpressing ASM, through parabiotic surgery. Elevated plasma ASM was found to enhance several neuropathological features in the young APP/PS1 mice by mediating the differentiation of blood-derived, pathogenic Th17 cells. Antibody-based immunotherapy targeting plasma ASM showed efficient inhibition of ASM activity in the blood of APP/PS1 mice and, interestingly, led to prophylactic effects on neuropathological features by suppressing pathogenic Th17 cells. Our data reveals insights into the potential pathogenic mechanisms underlying AD and highlights ASM-targeting immunotherapy as a potential strategy for further investigation.

Date: 2023
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DOI: 10.1038/s41467-023-37316-z

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