Tanshinones inhibit hIAPP aggregation, disaggregate preformed hIAPP fibrils, and protect cultured cells

Abstract

Misfolding and aggregation of amyloid peptides are the key pathological events in many neurodegenerative diseases. The development of effective inhibitors and drugs to prevent amyloid peptide aggregation is considered as an important therapeutic strategy for treating these diseases. We previously reported on tanshinones, ingredients from the Chinese herb Danshen (Salvia miltiorrhiza Bunge), as a potent inhibitor against amyloid-β_1–42 (Aβ) aggregation and toxicity. Considering the common structural and aggregation features, and the correlation of type II diabetes (T2D) and Alzheimer's disease (AD), herein we examine the inhibition activity of two tanshinone I (TS1) and IIA (TS2) components on the aggregation and toxicity of hIAPP_1–37 using combined experimental and computational approaches. Collective experimental data from ThT, CD, and AFM confirm that both tanshinones show comparable inhibition ability to reduce 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 hIAPP fibrils, but TS1 shows 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 hIAPP-induced cell toxicity. Molecular dynamics (MD) simulations further reveal that both tanshinones preferentially bind to β-sheets to prevent lateral association of hIAPP aggregates and thus to inhibit fibril growth, explaining experimental observations. This work discovers that tanshinones act as common inhibitors 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.