Copper metabolism and copper-mediated alterations in the metabolism of cultured astrocytes

Copper is an essential element that is required for a variety of important cellular functions. Since not only copper deficiency, but also excess of copper can seriously affect cellular functions, cellular copper metabolism is tightly regulated. Disturbances of copper homeostasis are the underlying defect of the inherited diseases Menkes and Wilson s disease and have also been linked to several neurodegenerative diseases including Alzheimer s disease and Parkinson s disease. Known astrocytes features strongly suggest a pivotal role of theses cells in the metal metabolism of the brain. Using astrocyte-rich primary cultures as model system, this thesis investigated the copper metabolism as well as copper-mediated alterations in the metabolism of astrocytes. Cultured astrocytes efficiently accumulated copper with saturable kinetics. The characteristics of the observed copper accumulation suggest that both copper transporter receptor 1 (Ctr1) and a Ctr1-independent mechanism are involved in astrocytic copper accumulation. Cultured astrocytes were also found to release copper in a time-, concentration- and temperature-dependent manner. Copper export from these cells most likely involves the copper-ATPase ATP7A. Thus, with being capable of both taking up and exporting copper, astrocytes possess the cellular machinery required to transport copper from the blood-brain barrier to the brain parenchyma. Cultured astrocytes were remarkable resistance against copper-induced toxicity. Nevertheless, prolonged copper treatment led to profound alterations in their metabolism. For example, copper accumulation by cultured astrocytes was accompanied by a stimulation of glycolytic flux, an increase in the cellular glutathione content and an acceleration of glutathione export. Such copper-mediated alterations in the metabolism of astrocytes may also occur in vivo, for example in copper overload conditions such in Wilson s disease and could either contribute to disease progression or serve as compensatory response to protect the brain against the toxic effects of an excess of copper.