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(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.
Department of Chemistry, Bar-Ilan University, Ramat-Gan, 52900, Israel.
Aviran
A
Amir
Eran
E
Shmuel
Rostislav
R
Zagalsky
Alon H
AH
Sayer
Yael
Y
Nadel
Bilha
B
Fischer
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical / Q000737:chemistry; D007501:Iron / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D009391:Nephelometry and Turbidimetry; D013873:Thionucleotides / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D013873:Thionucleotides; D017665:Hydroxyl Radical; D003300:Copper; D006861:Hydrogen Peroxide; D007501:Iron; D015032:Zinc