Bifunctional Copper Chelators Capable of Reducing Aβ Aggregation and Aβ-Induced Oxidative Stress

  • ACS Omega. 2024 Oct 17;9(43):43376-43384. doi: 10.1021/acsomega.4c03152.
Olga Krasnovskaya  1 ,  Daniil Abramchuk  1 ,  Alexander Vaneev  1  2 ,  Petr Gorelkin  2 ,  Maxim Abakumov  2  3 ,  Roman Timoshenko  2 ,  Ilia Kuzmichev  4 ,  Nelly Chmelyuk  2 ,  Veronika Vadehina  3  4 ,  Regina Kuanaeva  2 ,  Evgeniy Dubrovin  2  5 ,  Vasilii Kolmogorov  2 ,  Elena Beloglazkina  1 ,  Olga Kechko  6 ,  Vladimir Mitkevich  6 ,  Kseniya Varshavskaya  6 ,  Sergey Salikhov  2 ,  Alexander Erofeev  1  2
Affiliations
  • 1. Chemistry Department, Lomonosov Moscow State University, Leninskie gory 1,3, Moscow 119991, Russia.
  • 2. National University of Science and Technology (MISIS), Leninskiy prospect 4, Moscow 119049, Russia.
  • 3. Pirogov Russian National Research Medical University (RNRMU), Moscow 117997, Russia.
  • 4. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119991, Russia.
  • 5. Faculty of Physics, Lomonosov Moscow State University, Leninskie Gory 1, 2, Moscow 119991, Russia.
  • 6. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
PMID: 39493999 DOI: 10.1021/acsomega.4c03152
Abstract

Five bifunctional copper Chelating Agents, Alz-(1-5), designed to prevent beta-amyloid (Aβ) aggregation, were synthesized, and the leader compound (Alz-5) was chosen. Alz-5 acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity. Reactive Oxygen Species measurements provided by the Pt-nanoelectrode technique in single Aβ42-affected human neuroblastoma SH-SY5Y cells revealed significant antioxidant activity of Alz-5. AFM data obtained on Aβ42 fibrils clearly indicate the antiaggregating property of Alz-5. To gain insights into the changes in the physiomechanical properties of Aβ42-affected cells, as well as in order to evaluate the antiaggregating ability of Alz-5, Young's modulus mapping on living SH-SY5Y cells affected consequently by Aβ42 and Alz-5 was conducted, and the ability of Alz-5 to decrease cell rigidity induced by Aβ42 was indisputably proven. Low cell toxicity and antioxidating properties, in conjunction with AFM and SICM-based biophysical provided on Aβ42-affected SH-SY5Y cells, support Alz-5 as a potential inhibitor of Aβ aggregation.

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