Microglia and astroglia prevent oxidative stress-induced neuronal cell death: Implications for aceruloplasminemia

We partially characterized the transferrin-independent iron uptake (Tf-IU) of neuronal and glial cells in the previous report. In the present study, we further examined a mechanism of which glial cells protect neuronal cells against iron stress using neuron–microglia (N–MG) and neuron–astrocyte (N–AS) co-cultures. When each solely purified cell was treated with iron citrate, cell death occurred in N and MG. However, AS proliferated under the same condition. Both N–MG and N–AS co-cultures were effective in resistance to excessive iron. The total and specific Tf-IU activities of N–MG co-cultures similar to those of N did not increase in a density-dependent manner. Contrarily, the total activity of AS was extremely high and the specific activity was extremely low as a result of proliferation. Regarding of effect of co-cultures on H2O2-induced cell death, N–MG co-cultures were less effective, but N–AS co-cultures were more effective in protecting N from the oxidative stress. These results suggest that N–MG co-cultures suppress the Tf-IU and N–AS co-cultures stimulate AS proliferation to protect neuronal cells. Brain cells from aceruloplasminemia with mutations in the ceruloplasmin gene take up iron by Tf-IU. Therefore, the different mechanisms of neuronal cell protection by MG and AS may explain the pathophysiological observations in the brains of patient with aceruloplasminemia.