Diverse Ecdysterones Show Different Effects on Amyloid-β 42 Aggregation but All Uniformly Inhibit Amyloid-β 42 -Induced Cytotoxicity

Amyloid-β (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Aβ aggregation has long been one of the most promising strategies for AD treatment. Ecdysterones (ECRs) are steroidal hormones in insects and terrestrial plants that have high structural diversity and multiple beneficial pharmacological activities. Here, we studied the effects of six ECRs on Aβ aggregation and cytotoxicity. Two ECRs with an acetoxyl group at the 2 or 3 position and saturated chains as side groups showed apparent promotion of Aβ₄₂ fibrilization, resulting in less Aβ₄₂ oligomers in the samples. Another three with unsaturated side chains clearly inhibited Aβ aggregation and disaggregated preformed fibrils, but increased the Aβ₄₂ oligomer levels. Nevertheless, our MTT results showed that all ECRs tested inhibited Aβ₄₂-induced cytotoxicity. This protective activity may be partly attributable to ECR-mediated amelioration of Aβ₄₂-induced release of reactive oxygen species. Taken together, our findings suggest that ECRs, a series of natural compounds in many plants and insects, have therapeutic potential in AD and that the deduced structure-activity relationships may be beneficial in drug design for the treatment of AD and other amyloidoses.