Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β‐Amyloid Aggregation. (July 2014)

• Record Type: Journal Article
• Authors: Brogi, Simone; Butini, Stefania; Maramai, Samuele; Colombo, Raffaella; Verga, Laura; Lanni, Cristina; De Lorenzi, Ersilia; Lamponi, Stefania; Andreassi, Marco; Bartolini, Manuela; Andrisano, Vincenza; Novellino, Ettore; Campiani, Giuseppe; Brindisi, Margherita; Gemma, Sandra
• Is Part Of: CNS neuroscience & therapeutics. Volume 20:Number 7(2014)
• Page Start: 624
• Page End: 632
• Publication Date: 2014-07
• Subjects: Neuropharmacology -- Periodicals; Central nervous system -- Diseases -- Effect of drugs on -- Periodicals; 612.8
• DOI: 10.1111/cns.12290
• Languages: English
• ISSNs: 1755-5930

Abstract

<abstract abstract-type="main" id="cns12290-abs-0001"> <title>Summary</title> <sec id="cns12290-sec-0001" sec-type="section"> <title>Aims</title> <p>We recently described multifunctional tools (<bold>2a</bold>–<bold>c</bold>) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A<italic>β</italic> aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level.</p> </sec> <sec id="cns12290-sec-0002" sec-type="section"> <title>Methods</title> <p>We determined the inhibitory potency of <bold>2a–c</bold> on A<italic>β</italic><sub>1–42</sub> self‐aggregation, the interference of <bold>2a</bold> with the toxic A<italic>β</italic> oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A<italic>β</italic> toxicity was assessed for <bold>2a</bold> and <bold>2b</bold> on human neuroblastoma cells. The key interactions of <bold>2a</bold> with A<italic>β</italic> and with the A<italic>β</italic>‐preformed fibrils were computationally analyzed. <bold>2a</bold>–<bold>c</bold> toxicity profile was also assessed (human hepatocytes and mouse fibroblasts).</p> </sec> <sec id="cns12290-sec-0003" sec-type="section"> <title>Results</title> <p>Our prototypical pluripotent analogue <bold>2a</bold> interferes with A<italic>β</italic> oligomerization process thus reducing A<italic>β</italic> oligomers‐mediated toxicity in human neuroblastoma cells. <bold>2a</bold> also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of <bold>2a</bold>.</p> </sec> <sec id="cns12290-sec-0004" sec-type="section"> <title>Conclusion</title> <p>Converging analytical, biological, and <italic>in silico</italic> data explained the mechanism of action of <bold>2a</bold> on A<italic>β</italic><sub>1–42</sub> oligomers formation and against A<italic>β</italic>‐preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.</p> </sec> </abstract>