Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.

The impairment of mitophagy plays a key role in the pathology of Alzheimer's disease (AD). We previously demonstrated that ALT001 induces mitophagy via the alternative mitophagy pathway and ameliorates mitochondrial dysfunction and cognitive deficits in AD models. In this study, we synthesized a novel derivative, namely, ALT001-4a, by introducing an allyl group at the C13 position of ALT001. Compared with ALT001, ALT001-4a exhibited an approximately fivefold lower EC50 for inducing mitophagy, while maintaining low cytotoxicity, and it exerted this effect via the alternative mitophagy pathway. Similarly, ALT001-4a induced mitophagy in the hippocampus of mice at a fourfold lower dose than ALT001. Importantly, ALT001-4a successfully restored mitochondrial and cognitive function in both a cellular AD model and a 5xFAD AD model. These findings suggest that the structural modification of ALT001 can generate derivatives with superior potency and potential for treating Alzheimer's disease and that further optimization could enable the development of ALT001-4a as a viable therapeutic agent for AD.