Misfolding and aggregation of amyloid peptides are the key pathological events in many neurodegenerative diseases including Alzheimer’s disease (AD) and type 2 diabetes (T2D). Developing amyloid inhibitors to prevent amyloid aggregates is considered as a promising therapeutic strategy for treating these diseases. However, most of the existing amyloid inhibitors only inhibit the aggregation of specific amyloid peptide and show a strong sequence-dependent inhibition capability, making them difficult or impossible to be applicable to other amyloid peptides. Thus, it is both fundamentally and practically important for discovering some ligands that serve as a general amyloid inhibitor to inhibit the aggregation of different amyloid peptides. Herein, considering the common structural and aggregation features, and the correlation of T2D and AD, we discover and demonstrate tanshinones (two compounds of TS1 and TS2) - ingredients from the Chinese herb Danshen (Salvia miltiorrhiza Bunge) - which can impose a dual inhibition activity against the aggregation and toxicity of both full-length Aβ1-42 and hIAPP1-37 peptides using combined experimental and computational approaches. Collective experimental data from ThT, CD, and AFM confirm that both tanshinones show comparable inhibition ability to reduce both Aβ and hIAPP aggregates by inhibiting the fibrillation process and changing the fibrillogenesis pathway, leading to the formation of some amorphous aggregates. More importantly, both tanshinones are capable of disassembling preformed fibrils of Aβ and hIAPP, but TS1 shows the better potency in fibril dissembling than TS2. MTT and LDH assays also show that the tanshinones at very low concentrations of 5 µM can reduce the Aβ- and hIAPP-induced cell toxicity. Molecular dynamics (MD) simulations further reveal that both tanshinones preferentially bind to β-sheets to prevent Aβ-Aβ and hIAPP-hIAPP associations and thus to inhibit their fibril growth, explaining experimental observations. This work discovers that tanshinones act as common inhibitors (very few available today) to inhibit the aggregation of both hIAPP and Aβ, disaggregate preformed hIAPP and Aβ amyloid fibrils, and protect cells from hIAPP- and Aβ-induced toxicity, making them very promising agents against AD, T2D, and probably other amyloid-misfolding diseases.

Tanshinone as a dual amyloid Inhibitor against the aggregation and toxicity of both amyloid-β and hIAPP

255th National Meeting (2018)

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