Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer's disease
Byung Jo Choi1,2, Min Hee Park1,3, Kang Ho Park1,3
1KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu, South Korea.
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.
Insights
Plasma acid sphingomyelinase (ASM) accelerates Alzheimer's disease (AD) pathology by promoting pathogenic Th17 cells. Targeting plasma ASM with immunotherapy offers a potential prophylactic strategy against AD progression.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Acid sphingomyelinase (ASM) is linked to neurodegenerative diseases like Alzheimer's disease (AD).
- The precise function of plasma-derived ASM in AD pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of plasma ASM as a circulating factor in accelerating AD neuropathology.
- To explore ASM-targeting immunotherapy as a potential therapeutic strategy for AD.
Main Methods:
- Utilized parabiosis surgery to expose young APP/PS1 mice to blood from ASM-overexpressing mice.
- Assessed neuropathological features and Th17 cell differentiation in recipient mice.
- Investigated the efficacy of antibody-based immunotherapy targeting plasma ASM.
Main Results:
- Elevated plasma ASM enhanced AD neuropathological features in young APP/PS1 mice.
- Plasma ASM mediated the differentiation of pathogenic Th17 cells.
- ASM-targeted immunotherapy inhibited plasma ASM activity and demonstrated prophylactic effects by suppressing Th17 cells.
Conclusions:
- Plasma ASM acts as a circulating factor that exacerbates AD pathology.
- Pathogenic Th17 cell differentiation is a key mechanism by which plasma ASM promotes AD.
- ASM-targeting immunotherapy presents a promising avenue for AD prevention and treatment.
