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

Aviran Amir, Eran Shmuel, Rostislav Zagalsky, Alon H. Sayer, Yael Nadel, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)8539-8549
Number of pages11
JournalDalton Transactions
Volume41
Issue number28
DOIs
StatePublished - 28 Jul 2012

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