Identification of ortho catechol-containing isoflavone as a privileged scaffold that directly prevents the aggregation of both amyloid β plaques and tau-mediated neurofibrillary tangles and its in vivo evaluation

초록

In this study, polyhydroxyisoflavones that directly prevent the aggregation of both amyloid beta (A beta) and tau were expediently synthesized via divergent Pd(0)-catalyzed Suzuki-Miyaura coupling and then biologically evaluated. By preliminary structure-activity relationship studies using thioflavin T (ThT) assays, an ortho-catechol containing isoflavone scaffold was proven to be crucial for preventing both A beta aggregation and tau-mediated neurofibrillary tangle formation. Additional TEM experiment confirmed that ortho-catechol containing isoflavone 4d significantly prevented the aggregation of both A beta and tau. To investigate the mode of action (MOA) of 4d, which possesses an ortho-catechol moiety, H-1-N-15 HSQC NMR analysis was thoroughly performed and the result indicated that 4d could directly inhibit both the formation of A beta(42) fibrils and the formation of tau-derived neurofibrils, probably through the catechol-mediated nucleation of tau. Finally, 4d was demonstrated to alleviate cognitive impairment and pathologies related to Alzheimer's disease in a 5XFAD transgenic mouse model.

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