The link between copper homeostasis and Alzheimer's disease as a route to therapy

Abstract

Ageing is a natural process, which is characterised by progressive decline in physiological functions and increased susceptibility to disease and death. Brain is particularly susceptible to structural and functional changes, which is more evident in disorders associated with ageing such as Alzheimer disease (AD). Copper is necessary for the protection against oxidative stress, energy production and neurotransmitter processing in the brain. However, higher copper levels can increase oxidative stress, resulting in neuronal damage. In order to avoid copper induced cytotoxicity, cells have to regulate copper levels through distribution into three intracellular pathways. By identifying changes in the copper pathways in the healthy and AD brain and by estimating the effects of copper chelation or supplementation in model cell line a better understanding of copper function in the brain will be obtained. In order to accomplish that copper, activity and protein levels of cytochrome c oxidase (COX) and superoxide dismutase (SOD) were measured in the healthy, AD brain and in HEK293 cell treated with copper chelators or supplemented with copper. Copper concentration was significantly decrease by more than 40% in healthy ageing brain and in the AD brain. Copper loss did not seem to affect the activity or protein level of the COX and SOD, since their levels were significantly increased in the ageing and AD brain. On the other hand, cells treated with copper chelators for three days faced a more than 75% decrease in intracellular copper concentration, which led to a more than 85% inhibition of the COX and SOD activity. Copper levels should be regulated properly in order to meet body’s metabolic demands and avoid cytotoxicity. Brain seems to have a mechanism where its energy demands have to be fulfilled even under low copper concentrations. Whereas, the prolonged and severe copper loss can dramatically affect the energy production and antioxidant defence systems which could be fatal to the cells.