Modelling Copper Binding to the Amyloid-β Peptide in Alzheimer

2010 ◽  
Vol 63 (3) ◽  
pp. 345 ◽  
Author(s):  
V. Chandana Epa ◽  
Victor A. Streltsov ◽  
Joseph N. Varghese
Keyword(s):  
Reactive Oxygen Species ◽  
Binding Site ◽  
Reactive Oxygen Species Generation ◽  
Computational Modelling ◽  
Amyloid Β ◽  
Reactive Oxygen ◽  
Oxidative Modification ◽  
Amyloid Β Peptide ◽  
Oxygen Species ◽  
Copper Binding

Oxidative modification due to reactive oxygen species generated by Cu2+ bound to the amyloid-β peptide may be one of the sources of neurodegeneration observed in Alzheimer’s disease. Understanding the structure and function of the copper binding site can assist in the design of effective therapeutics. This paper highlights some of the most significant recent developments in computational modelling studies of the structure of the binding site and reaction mechanisms of reactive oxygen species generation.

scholarly journals Hybrid Bis-Histidine Phenanthroline-Based Ligands to Lessen Aβ-Bound Cu ROS Production: An Illustration of Cu(I) Significance

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7630
Author(s):  
Marielle Drommi ◽  
Clément Rulmont ◽  
Charlène Esmieu ◽  
Christelle Hureau
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Copper Complexes ◽  
Amyloid Β ◽  
Reactive Oxygen ◽  
Complete Characterization ◽  
Amyloid Β Peptide ◽  
Oxygen Species ◽  
Hybrid Ligands

We here report the synthesis of three new hybrid ligands built around the phenanthroline scaffold and encompassing two histidine-like moieties: phenHH, phenHGH and H’phenH’, where H correspond to histidine and H’ to histamine. These ligands were designed to capture Cu(I/II) from the amyloid-β peptide and to prevent the formation of reactive oxygen species produced by amyloid-β bound copper in presence of physiological reductant (e.g., ascorbate) and dioxygen. The amyloid-β peptide is a well-known key player in Alzheimer’s disease, a debilitating and devasting neurological disorder the mankind has to fight against. The Cu-Aβ complex does participate in the oxidative stress observed in the disease, due to the redox ability of the Cu(I/II) ions. The complete characterization of the copper complexes made with phenHH, phenHGH and H’phenH’ is reported, along with the ability of ligands to remove Cu from Aβ, and to prevent the formation of reactive oxygen species catalyzed by Cu and Cu-Aβ, including in presence of zinc, the second metal ions important in the etiology of Alzheimer’s disease. The importance of the reduced state of copper, Cu(I), in the prevention and arrest of ROS is mechanistically described with the help of cyclic voltammetry experiments.

Activation of the neuronal c-Abl tyrosine kinase by amyloid-β-peptide and reactive oxygen species

2004 ◽  
Vol 17 (2) ◽  
pp. 326-336 ◽  
Author(s):  
Alejandra R. Alvarez ◽  
Pablo C. Sandoval ◽  
Nancy R. Leal ◽  
Paula U. Castro ◽  
Kenneth S. Kosik
Keyword(s):  
Reactive Oxygen Species ◽  
Tyrosine Kinase ◽  
Amyloid Β ◽  
Reactive Oxygen ◽  
Amyloid Β Peptide ◽  
Oxygen Species ◽  
Abl Tyrosine Kinase

scholarly journals Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation

Marine Drugs ◽  
2020 ◽  
Vol 18 (6) ◽  
pp. 335
Author(s):  
Francisca García ◽  
Pedro Lobos ◽  
Alejandra Ponce ◽  
Karla Cataldo ◽  
Daniela Meza ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Therapeutic Agent ◽  
Antioxidant Properties ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Amyloid Β Peptide ◽  
Carotenoid Pigment ◽  
Oxygen Species ◽  
Cellular Viability ◽  
Mitochondrial Reactive Oxygen Species

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca2+ concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca2+ dysregulation. Here, we studied whether ASX protects neurons from N-methyl-D-aspartate (NMDA)-induced excitotoxicity, a noxious process which decreases cellular viability, alters gene expression and promotes excessive mROS production. Incubation of the neuronal cell line SH-SY5Y with NMDA decreased cellular viability and increased mitochondrial superoxide production; pre-incubation with ASX prevented these effects. Additionally, incubation of SH-SY5Y cells with ASX effectively reduced the basal mROS production and prevented hydrogen peroxide-induced cell death. In primary hippocampal neurons, transfected with a genetically encoded cytoplasmic Ca2+ sensor, ASX also prevented the increase in intracellular Ca2+ concentration induced by NMDA. We suggest that, by preventing the noxious mROS and Ca2+ increases that occur under excitotoxic conditions, ASX could be useful as a therapeutic agent in neurodegenerative pathologies that involve alterations in Ca2+ homeostasis and ROS generation.

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