title: Diverse ecdysterones show different effects on amyloid-β42 aggregation but all uniformly inhibit amyloid-β42-induced cytotoxicity.
abstract: 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 A&beta42-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.
authors.affiliation: Tsinghua University School of Medicine, Haidian District, Beijing, China.
authors.forename: Shi-Gao
authors.initials: SG
authors.lastname: Yang
authors.forename: Xi
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiao-Sia
authors.initials: XS
authors.lastname: Sun
authors.forename: Tie-Jun
authors.initials: TJ
authors.lastname: Ling
authors.forename: Ying
authors.initials: Y
authors.lastname: Feng
authors.forename: Xue-Ying
authors.initials: XY
authors.lastname: Du
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Di
authors.initials: D
authors.lastname: Xue
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Rui-Tian
authors.initials: RT
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D004441:Ecdysterone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D017510:Protein Folding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; C075222:amyloid beta-protein (1-42); D004441:Ecdysterone