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journal article·2026-04Open access

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

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

Advanced Science· Volume 13· Issue 24
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Source abstract

Abstract

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.
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Research context

Biomaterials

OpenAlex topics: Alzheimer's disease research and treatments · Autophagy in Disease and Therapy · Sirtuins and Resveratrol in Medicine

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Clinical Molecular Biology University of Oslo and Akershus University Hospital Lørenskog Norway

Department of Clinical Chemistry Faculty of Allied Health Sciences Chulalongkorn University Pathum Wan Bangkok Thailand

Department of Cellular and Molecular Biology Margarita Salas Center For Biological Research Spanish National Research Council Madrid Madrid Spain

Cleveland Clinic Genome Center Cleveland Clinic Research Cleveland Clinic Cleveland Ohio USA

Department of Genomic Sciences and Systems Biology Cleveland Clinic Research, Cleveland Clinic Cleveland Ohio USA

Institute of Quantum Biophysics Sungkyunkwan University Suwon Gyeonggi Republic of Korea

Department of Biophysics Sungkyunkwan University Suwon Gyeonggi Republic of Korea

Department of Intelligent Precision Healthcare Convergence Sungkyunkwan University Suwon Gyeonggi Republic of Korea

UK Dementia Research Institute at the University of Cambridge Cambridge UK

Department of Clinical Neurosciences University of Cambridge Cambridge UK

MindRank AI Ltd. Hangzhou Zhejiang P. R. China

Department of Microbiology and Immunology School of Medicine Institute of Geriatric Immunology School of Medicine Jinan University Guangzhou P. R. China

Department of Systems Biomedical Sciences School of Medicine Jinan University Guangzhou P. R. China

Guangdong‐Hong Kong‐Macau Great Bay Area Geroscience Joint Laboratory Guangzhou P. R. China

State Key Laboratory of Mechanism and Quality of Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao P. R. China

School of Basic Medical Sciences Lanzhou University Lanzhou Gansu P. R. China

Department of Clinical Medicine (K1) University of Bergen Bergen Norway

Department of Neurosurgery Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine Shanghai P. R. China

Hong Kong Longevity Science Laboratory Limited Hong Kong Science Park Hong Kong SAR P. R. China

Department of Neurobiology Hellenic Pasteur Institute Athens Greece

Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA Cleveland Clinic Lerner College of Medicine, Case Western Reserve University Cleveland Ohio USA

Department of Physiology Medical School National and Kapodistrian University of Athens Athens Greece

Institute of Neurology Huashan Hospital Fudan University Shanghai P. R. China

National Center for Neurological Disorders Huashan Hospital Fudan University Shanghai P. R. China

National Clinical Research Center for Aging and Medicine Huashan Hospital Fudan University Shanghai P. R. China

Funding

Norges Forskningsråd · National Natural Science Foundation of China · European Research Council · National Research Foundation · Basic and Applied Basic Research Foundation of Guangdong Province · Nasjonalforeningen for Folkehelsen · Akershus Universitetssykehus

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