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

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(2)O(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 (1)H-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(2)O(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.

ATP-γ-S-(α,β-CH2) protects against oxidative stress and amyloid beta toxicity in neuronal culture

“…Amyloid-beta (1e42) oligomers were prepared according to Amir et al [10]. Briefly, Ab 42 (3 mg) was dissolved in 10 mM NaOH, sonicated for 3 min, and then freeze-dried.…”

“…The purine nucleotide scaffold contains metal binding sites at both the phosphate chain and purine ring (N7-nitrogen atom), and makes a natural divalent metal ion chelator [8]. Indeed we showed that nucleotides are efficient Fe(II)-chelators [10].…”

“…1) effectively dissolved Ab 40 -Cu(I) and Ab 42 -Cu(I)/Zn(II) aggregates [10] better than ATP-g-S or ATP, as monitored by 1 H NMR, TEM, and turbidity assays. Furthermore, ATP-g-S-(a,b-CH 2 ) re-solubilized Ab 40 eCu(II) aggregates more efficiently than EDTA [10].…”

“…The highly promising properties of ATP-g-S-(a,b-CH 2 ) as a Fenton reaction inhibitor [10], an effective ion chelator [16], a powerful agent for in-vitro dissolution of Ab 40/42 -M(II) oligomers and aggregates [10], together with its enzymatic stability, and its high activity at P2Y11-R [12], encouraged us to explore the potential of ATP-g-S-(a,b-CH 2 ) for the rescue of primary neurons subjected to insults typical of Alzheimer's disease.…”

Design, Synthesis and Biological Evaluation of 1-Phenyl-Ethanone Derivatives for Multi-Targeted Treatment of Alzheimer's Disease

“…Some experiments also find that the level of metal ions in AD patients are 3-7 folds higher than that of healthy individuals [10], it indicated that the dyshomeostasis of biometals (Fe, Cu, Zn) in the brain may contribute to AD pathology [11]. Clioquinol (a classic metal chelator used as antifungal drug and antiprotozoal drug), had been tested to treat AD [12,13]. The phase II clinical trials suggested that clioquinol could halt cognitive decline in AD, possibly owing to its ability to chelate copper and zinc ions.…”