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.