Nucleoside-5′-phosphorothioate analogues are biocompatible antioxidants dissolving efficiently amyloid beta-metal ion aggregates

Amyloid beta (Aβ) peptide is known to precipitate and form aggregates with zinc and copper ions in vitro and, in vivo in Alzheimer's disease (AD) patients. Metal-ion-chelation was suggested as therapy for the metal-ion-induced Aβ aggregation, metal-ion overload, and oxidative stress. In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we tested a series of nucleoside 5′-phosphorothioate derivatives as re-solubilization agents of Cu ⁺/Cu ²⁺/Zn ²⁺-induced Aβ-aggregates, and inhibitors of Fenton reaction in Cu ⁺ or Fe ²⁺/H ₂O ₂ system. The most promising chelator in this series was found to be APCPP-γ-S. This nucleotide was found to be more efficient than EDTA in re-solubilization of Aβ ₄₀-Cu ²⁺ aggregates as observed by the lower diameter, d _H, (86 vs. 64 nm, respectively) obtained in dynamic light scattering measurements. Likewise, APCPP-γ-S dissolved Aβ ₄₀-Cu ⁺ and Aβ ₄₂-Cu ²⁺/Zn ²⁺ aggregates, as monitored by ¹H-NMR and turbidity assays, respectively. Furthermore, addition of APCPP-γ-S to nine-day old Aβ ₄₀-Cu ²⁺/Zn ²⁺ aggregates, resulted in size reduction as observed by transition electron microscopy (diameter reduction from 2.5 to 0.1 μm for Aβ ₄₀-Cu ²⁺ aggregates). APCPP-γ-S proved to be more efficient than ascorbic acid and GSH in reducing OH radical production in Fe ²⁺/H ₂O ₂ system (IC ₅₀ values 85, 216 and, 92 μM, respectively). Therefore, we propose APCPP-γ-S as a potential AD therapy capable of both reducing OH radical production and re-solubilization of Aβ _40/42-M ⁿ⁺ aggregates.