Combination of baicalein and trans‐chalcone synergistically reduces amyloid beta and its toxicity in yeast

Abstract

AbstractBackgroundThere has been a long quest to uncover effective therapeutic strategy to prevent or cure AD as current strategies only support as palliative care. This study utilizes unmodified and genetically modified Saccharomyces cerevisiae as model organisms to screen and find potential natural bioactive compounds that can reduce the levels of amyloid beta and associated toxicity.MethodsEleven selected naturally occurring bioactive compounds namely mangiferin, quercetin, rutin, resveratrol, epigallocatechin gallate (EGCG), urolithin A, oleuropein, rosmarinic acid, salvianolic acid B, baicalein and trans‐chalcone at specific concentration (50µM) were screened for their ability to change intracellular green fluorescent protein (GFP) tagged Aβ42 levels, in vivo anti‐amyloid properties using thioflavin‐S fluorescent dye and induce heat stress response using the yeast heat stress reporter that expresses mCherry red fluorescent protein under control of a heat shock promoter containing heat shock elements (HSEs). Furthermore, the two compounds with highest activity in all three screens were combined together in varying concentrations of each to study the underlying combination ability to reduce GFP‐Aβ42, their effect on growth, turnover of native Aβ42 and reactive oxygen species.ResultsThe bioactive compounds reduced intracellular GFP‐Aβ42 levels (except mangiferin) and intracellular amyloid fibrils (except resveratrol and EGCG) in yeast models significantly with highest effect shown by baicalein and trans‐chalcone. Among the bioactive compounds, quercetin, rutin, rosmarinic acid, baicalein and trans‐chalcone significantly induced heat stress reporter with highest effect demonstrated by baicalein and trans‐chalcone. Furthermore, the combinations of baicalein and trans‐chalcone showed synergistic ability to reduce GFP‐Aβ42. Although some of the combinations were found growth inhibitory, a combination of 50μM trans‐chalcone and 30μM baicalein was found to be cytoprotective as well as an effective reducer of GFP‐Aβ42. In addition, the combination of the two compounds showed synergy in reducing ROS in yeast cells expressing native Aβ42 and reduced the Aβ42 protein levels by nearly 80%.ConclusionThe findings of the study suggest that the combination of baicalein and trans‐chalcone can be a therapeutic strategy to cure or at least prevent AD. However, further studies are recommended to ascertain that similar cytoprotective activity is observed in humans and optimization of dosage to observe best effect.