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 Abeta 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 Abeta1-42 self-aggregation, the interference of 2a with the toxic Abeta oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Abeta toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Abeta and with the Abeta-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 Abeta oligomerization process thus reducing Abeta 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 Abeta1-42 oligomers formation and against Abeta-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues