TY - JOUR
T1 - Disease-modifying anti-Alzheimer's drugs
T2 - Inhibitors of human cholinesterases interfering with β-amyloid aggregation
AU - Brogi, Simone
AU - Butini, Stefania
AU - Maramai, Samuele
AU - Colombo, Raffaella
AU - Verga, Laura
AU - Lanni, Cristina
AU - De Lorenzi, Ersilia
AU - Lamponi, Stefania
AU - Andreassi, Marco
AU - Bartolini, Manuela
AU - Andrisano, Vincenza
AU - Novellino, Ettore
AU - Campiani, Giuseppe
AU - Brindisi, Margherita
AU - Gemma, Sandra
PY - 2014
Y1 - 2014
N2 - Aims: We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ 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 Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-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 Aβ oligomerization process thus reducing Aβ 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 Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
AB - Aims: We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ 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 Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-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 Aβ oligomerization process thus reducing Aβ 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 Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
KW - Alzheimer's disease
KW - Amyloid beta oligomers
KW - Amyloid beta peptides
KW - Cholinesterase inhibitors
KW - Molecular dynamics
KW - Multifunctional ligands
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UR - http://www.scopus.com/inward/citedby.url?scp=84902481986&partnerID=8YFLogxK
U2 - 10.1111/cns.12290
DO - 10.1111/cns.12290
M3 - Article
C2 - 24935788
AN - SCOPUS:84902481986
VL - 20
SP - 624
EP - 632
JO - CNS Neuroscience and Therapeutics
JF - CNS Neuroscience and Therapeutics
SN - 1755-5930
IS - 7
ER -