HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity

Amyloid deposits of misfolded amyloid-beta protein (A beta) on neuronal cells are a pathological hallmark of Alzheimer's disease (AD). Prevention of the abnormal A beta aggregation has been considered as a promising therapeutic strategy for AD treatment. To prevent reinventing the wheel, we proposed to search the existing drug database for other diseases to identify potential A beta inhibitors. Herein, we reported the inhibitory activity of HP-beta-cyclodextrin (HP-beta-CD), a well-known sugar used in drug delivery, genetic vector, environmental protection and treatment of Niemann-Pick disease type C1 (NPC1), against A beta(1-42) aggregation and A beta-induced toxicity, with the aim of adding a new function as a sugar-based A beta inhibitor. Experimental data showed that HP-beta-CD molecules were not only nontoxic to cells, but also greatly inhibited A beta fibrillization and reduced A beta-induced toxicity in a concentration-dependent manner. At an optimal molar ratio of Ab : HP-beta-CD = 1 : 2, HP-beta-CD enabled the reduction of 60% of A beta fibrils and increased the cell viability to 92%. Such concentration-dependent inhibitor capacity of HP-beta-CD was likely attributed to several combined effects, including the enhancement of A beta-HP-beta-CD interactions, prevention of structural transition of A beta peptides towards beta-sheet structures, and reduction of self-aggregation of HP-beta-CD. In parallel, molecular simulations further revealed the atomic details of HP-beta-CD interacting with the A beta oligomer, showing that HP-beta-CD had a high tendency to interact with hydrophobic residues of Ab in two beta-strands and the N-terminal tail. More importantly, we identified that the inner hydrophobic cavity of HP-beta-CD was a key active site for A beta inhibition. Once the inner cavity of HP-beta-CD was blocked by a small hydrophobic molecule of ferulic acid, HP-beta-CD completely lost its inhibition capacity against A beta. Given the already established pharmaceutical functions of HP-beta-CD in drug delivery, our findings suggest that HP-beta-CD has great potential to be designed as a sugar-based Ab inhibitor.