Aromadendrin: A Dual Amyloid Promotor to Accelerate Fibrillization and Reduce Cytotoxicity of Both Amyloid-β and hIAPP
Abnormal aggregation of misfolded amyloid proteins into amyloid fibrils is associated with many neurodegenerative diseases, including Alzheimer’s disease (AD) and Type II diabetes (T2D). In principle, any strategy to alter the amyloid aggregation process is considered as a potential therapeutic treatment for these diseases. Significant efforts and progress have been made to develop amyloid inhibitors that can slow down and prevent amyloid aggregation process. However, much less research has been reported to discover general amyloid promotors to accelerate amyloid progress and remodel toxic amyloids. Here, we for the first time reported a repurposing drug of aromadendrin as a dual amyloid promotor to be effective in accelerating amyloid aggregation/fibrillization and reducing neuroblastoma/insulinoma toxicity of both Aβ42 (associated with AD) and hIAPP37 (associated with T2D). ThT, AFM, and CD results showed that addition of aromadendrin to amyloid solutions with 1 to 5 molar ratios caused significant acceleration in Aβ42 fibrillization by 86-114% and hIAPP fibrillization by 20-68% as evidenced by shortening or bypassing the lag phase, promoting the growth phase, and rapidly converting amyloid species towards the higher ordered β-structure-rich aggregates. Seeding experiments further revealed that aromadendrin is more effective to accelerate the aggregation and structural conversion of amyloid species at the lag and early growth phases, but unable to escalate the fibrillization of higher order protofibrils. Moreover, MTT and LDH cell assays showed that aromadendrin-treated cell samples enabled to rescue cells from both Aβ- and hIAPP-induced toxicity by increasing 12%-15% (Aβ) and 10%-49% (hIAPP) of cell viability and reducing 45%-67% (Aβ) and 10%-30% (hIAPP) of cell apoptosis. LUVs assays explained the protection role of aromadendrin in cell toxicity due to the suppression of toxic oligomer formation thus the decrease of membrane leakage. This work offers a new strategy for discovering aromadendrin as amyloid promotors, not as amyloid inhibitors, to accelerate amyloid formation and remedy amyloid-mediated toxicity for both Aβ and hIAPP, and the sequence-independent promotion effect of aromadendrin could be also applied to other amyloid proteins.