2. Academic Validation
  3. Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease

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

  • Nat Commun. 2023 Mar 24;14(1):1631. doi: 10.1038/s41467-023-37316-z.
Byung Jo Choi # 1 2,  Min Hee Park # 1 3,  Kang Ho Park 1 3,  Wan Hui Han 1 3,  Hee Ji Yoon 1 3,  Hye Yoon Jung 1 3,  Ju Yeon Hong 1 3,  Md Riad Chowdhury 1 3,  Kyung Yeol Kim 1 3,  Jihoon Lee 4,  Im-Sook Song 4,  Minyeong Pang 5,  Min-Koo Choi 5,  Erich Gulbins 6,  Martin Reichel 7,  Johannes Kornhuber 7,  Chang-Won Hong 3,  Changho Kim 8,  Seung Hyun Kim 9,  Edward H Schuchman 10,  Hee Kyung Jin 11 12,  Jae-Sung Bae 13 14
Affiliations

Affiliations

  • 1 KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea.
  • 2 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
  • 3 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea.
  • 4 BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, Vessel-Organ Interaction Research Center (VOICE), College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, South Korea.
  • 5 College of Pharmacy, Dankook University, Cheon-an, South Korea.
  • 6 Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
  • 7 Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
  • 8 Department of Emergency Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, South Korea.
  • 9 Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.
  • 10 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11 KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea. hkjin@knu.ac.kr.
  • 12 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea. hkjin@knu.ac.kr.
  • 13 KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea. jsbae@knu.ac.kr.
  • 14 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea. jsbae@knu.ac.kr.
  • # Contributed equally.
PMID: 36959217 DOI: 10.1038/s41467-023-37316-z
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.

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