The Flavonoid Derivative 2-(4' Benzyloxyphenyl)-3-hydroxy-chromen-4-one Protects Against Aβ42-Induced Neurodegeneration in Transgenic Drosophila: Insights from In Silico and In Vivo Studies

In the pathogenesis of Alzheimer's disease (AD), it is well established that the self-association of A beta peptides into amyloid fibrils and/or plaque like aggregates causes neurotoxicity. As there is no cure for AD till date, identification of specific compounds that either inhibit the formation of A beta-fibrils or help in the dissolution of already formed amyloid plaques makes an appealing therapeutic and preventive strategy in the development of drugs. In the present study, four synthetic flavonoid derivatives (1, 2, 3 and 4) were examined for docking studies with Amyloid beta (PDB Code: 1IYT) and Amyloid fibril (PDB Code: 2BEG). Of these, compound 1 and 4 were found to be potential inhibitors, as supported by computational molecular docking studies with adequate pharmacokinetic properties. Compound 1 was further tested in vivo in transgenic AD model of Drosophila. The disease causing human A beta(42) peptide was expressed in the compound eye by driving UAS-A beta(42) with ey-GAL4, which caused severe degeneration in eye tissues ranging from loss of bristles, ommatidial holes to severe ommatidial disruption as revealed by digital camera imaging and scanning electron microscopy. When the A beta(42) expressing larvae were grown in medium containing Compound 1, similar to 70 % rescue of the rough eye phenotype was observed at 75 and 100 mu M concentrations. This is further corroborated by significant reduction in amyloid plaques in eye imaginal disks of compound 1 treated larvae as revealed by immuno-confocal imaging studies. Further, rescue of locomotor deficit and improved life span in compound 1 treated A beta flies also confirm the neuroprotective activity of this compound. Thus, our results support the neuroprotective efficacy of compound 1 in preventing A beta(42)-induced neurotoxicity in vivo and identify it as a future therapeutic agent against AD.