Reactive oxygen species (ROS) formed from copper-related processes can induce oxidative damage to living cells, which is one of the inducements of neurodegenerative disease including Alzheimer's disease. ROS are a class of reactive one-electron reduction products formed from oxygen (Eq. 1) as a result of normal cellular metabolism. [1,2] Aberrant concentrations of copper ions in human brain can accelerate excessive ROS formation via Fenton reaction (Eq. 2). Copper is an essential trace element for the development and functioning of central nervous system, and its concentration in human brain can reach 100 μM. Copper ions are bound to biomolecules in vivo, while abnormal homeostasis can lead to liberation of them. The amyloid cascade hypothesis proposes that amyloid−β (Aβ), formed from aberrant hydrolysis of amyloid precursor protein, can capture copper ions from other biomolecules. [3] The resulting product (Cu − Aβ complex) also possesses catalytic activity for ROS formation (Eq. 3).O2→+e−O2∙−→+e−+2H+H2O2→+e−∙OH+OH−

An available approach for reducing copper-related ROS formation is copper ions chelation. However, some challenges still remain, including high toxicity, redox inertness, blood–brain barrier (BBB) permeability, suitable pharmacokinetics and stability of the complexing compounds, and selectivity toward copper ions in the presence of other metal ions. [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13]] Natural compounds with complexing property can be candidates for reducing formations of copper-related ROS associated with AD, as their low toxicity and biocompatibility. Alginate, a natural macromolecule complexing agent, was used as a chelator to remove heavy metal ions before. In vitro experiments confirms that alginate can be available for reducing ROS damage and inhibiting Cu − Aβ complex formation. [14,15] However, the high viscosity and large radii limit its in vivo applications.

Alginate oligosaccharides (AOSs), depolymerized from alginate, are oligomers with a polymerization degree of 2–25. [[16], [17], [18]] GA is one of the main components of AOSs. Previous studies have confirmed that GA is available for metal ions chelation and the resulting product exhibit egg-box structure. [19] In addition, as a bioactive compound, GA also displays a variety of physiological properties, such as immunosuppressive (G2013), neuroprotective, anti-oxidative, and so on. [[19], [20], [21], [22], [23]] All of these point to that GA may be available for inhibiting ROS formation and making clearance of existing ROS in vivo. However, to our knowledge, few has been reported.

Here, we investigated the effect of GA in reducing copper-related ROS formation and capturing Aβ from the Cu − Aβ complex. As metal ions and Aβ are accumulated in AD brain, we also tested the efficiency of GA in reducing ROS formation in solutions containing Aβ and a variety of metal ions. To test the potential of GA for in vivo applications, the toxicity of GA was analyzed using human liver hepatocellular carcinoma (HepG2) cells, and the efficiency of GA in reducing neuro damage caused by copper-related ROS were tested using human neuroblastoma (SH − SY5Y) cells as a model cell.