Disease-Modifying Anti-Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β-Amyloid Aggregation

Aims: We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A beta aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. Methods: We determined the inhibitory potency of 2a-c on A beta(1-42) self-aggregation, the interference of 2a with the toxic A beta oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A beta toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A beta and with the A beta-preformed fibrils were computationally analyzed. 2a-c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Results: Our prototypical pluripotent analogue 2a interferes with A beta oligomerization process thus reducing A beta oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a. Conclusion: Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A beta(1-42) oligomers formation and against A beta-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.