The Mitochondrial Guardian α‐Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK‐SARM1‐ULK1 Axis

High consumption of colorful fruits and vegetables correlates with low dementia risk, but the exact molecules and the underlying biological mechanisms governing their bioactive profiles are largely unknown. Using a 10-year observational cohort study coupled with an AI-driven systems pharmacology platform, we identified a natural triterpenoid compound found in colorful fruits and vegetables, α-Amyrin (αA), as a therapeutic candidate for Alzheimer's disease (AD). The efficacy of αA in treating the symptoms of AD, such as Tau tangles, damaged mitochondria, and memory loss, was examined using cross-species models; αA retained memory in AD-like animal models while also strongly inhibiting Tau pathology, especially p-Tau217, in a cellular 'Tau seeding' system and in Tau[P301S] mice, followed by validation using a human 3D microfluidic system. At molecular level, αA is a robust mitochondrial regulator, enhancing mitochondrial stress resilience and activation of mitophagy. Mechanistically, αA inhibits dual leucine zipper kinase (DLK), leading to the inhibition of DLK-Sterile Alpha and TIR Motif Containing 1 (SARM1)-dependent neurodegeneration; this inhibition frees unc-51 Like Autophagy Activating Kinase 1 (ULK1) from the ULK1-SARM1 complex, allowing it to participate in autophagy/mitophagy. αA also shows strong translational potential with a 10.1 h half-life and the ability to cross the blood-brain barrier. Our results indicate that αA may act as a mitochondrial guardian against AD via modulating the DLK-SARM1-ULK1-autophagy/mitophagy axis while further preclinical and clinical studies are warranted.

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Publication Details

Journal
Advanced Science
Published
2026-01-22
DOI
https://doi.org/10.1002/advs.202512374
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

The Mitochondrial Guardian α‐Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK‐SARM1‐ULK1 Axis

Xurui Jin, N. Tavernarakis, Konstantinos Palikaras, Juan Ignacio Jiménez‐Loygorri et al.
Advanced Science
Alzheimer's disease research and treatments
article

The Mitochondrial Guardian α‐Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK‐SARM1‐ULK1 Axis

Xurui Jin, N. Tavernarakis, Konstantinos Palikaras, Juan Ignacio Jiménez‐Loygorri, Shuqin Cao, Sofie Lautrup, Ni Li, Kristina Xiao Liang, Annabel E. Smith, Huanxing Su, Rebecca Matsas, Qian Zhao, Yunguang Qiu, William A. McEwan, Florentia Papastefanaki, Yahyah Aman, Ang Li, Jun‐Ping Pan, You Jung Kang, CM van Duijn, Olympia Apokotou, Junjie Huang, Hansang Cho, Patricia Boya, Lipeng Mao, Hangge Yang, Anbin Chen, Feixiong Cheng, Maria Jose Donate Lagartos, Ding Ding, Tin Cho Cheung, Oscar Junhong Luo, Juan Yi, Guobing Chen, Khanh Van Do, Evandro F. Fang
article en

Abstract

High consumption of colorful fruits and vegetables correlates with low dementia risk, but the exact molecules and the underlying biological mechanisms governing their bioactive profiles are largely unknown. Using a 10-year observational cohort study coupled with an AI-driven systems pharmacology platform, we identified a natural triterpenoid compound found in colorful fruits and vegetables, α-Amyrin (αA), as a therapeutic candidate for Alzheimer's disease (AD). The efficacy of αA in treating the symptoms of AD, such as Tau tangles, damaged mitochondria, and memory loss, was examined using cross-species models; αA retained memory in AD-like animal models while also strongly inhibiting Tau pathology, especially p-Tau217, in a cellular 'Tau seeding' system and in Tau[P301S] mice, followed by validation using a human 3D microfluidic system. At molecular level, αA is a robust mitochondrial regulator, enhancing mitochondrial stress resilience and activation of mitophagy. Mechanistically, αA inhibits dual leucine zipper kinase (DLK), leading to the inhibition of DLK-Sterile Alpha and TIR Motif Containing 1 (SARM1)-dependent neurodegeneration; this inhibition frees unc-51 Like Autophagy Activating Kinase 1 (ULK1) from the ULK1-SARM1 complex, allowing it to participate in autophagy/mitophagy. αA also shows strong translational potential with a 10.1 h half-life and the ability to cross the blood-brain barrier. Our results indicate that αA may act as a mitochondrial guardian against AD via modulating the DLK-SARM1-ULK1-autophagy/mitophagy axis while further preclinical and clinical studies are warranted.

Advanced Science
Cleveland Clinic (US), Norwegian Institute of Public Health (NO), University of Crete (GR), University of Fribourg (CH), Chulalongkorn University (TH), Jinan University (CN), University of Oslo (NO), National and Kapodistrian University of Athens (GR), University of Macau (MO), University of Cambridge (GB), Akershus University Hospital (NO), Hong Kong Science and Technology Parks Corporation (HK), XinHua Hospital (CN), Cleveland Clinic Lerner College of Medicine (US), University of Oxford (GB), Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN), Pasteur Hellenic Institute (GR), UK Dementia Research Institute (GB), National Research Council (LK), Huashan Hospital (CN), Zhejiang Medicine (China) (CN), University of Bergen (NO), Lanzhou University (CN), Sungkyunkwan University (KR), Foundation for Research and Technology Hellas (GR)
National Research Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Chulalongkorn University, NordForsk, Norges Forskningsråd, Université de Fribourg, Akershus Universitetssykehus, Nasjonalforeningen for Folkehelsen, Ministry of Science and ICT, South Korea, Basic and Applied Basic Research Foundation of Guangdong Province
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Alzheimer's disease research and treatments
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