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.