Neurotoxic effects of apolipoprotein E4 are mediated via dysregulation of calcium homeostasis

The association of the E4 allele of apolipoprotein E (apoE4) as a genetic risk factor for Alzheimer's disease (AD) has been well established. Although recent studies in neuronal cell lines and transgenic mice have shown that apoE4 promotes neurodegeneration, the mechanisms through which apoE4 impairs neuronal viability are not completely understood. In this context, the main objective of the present study was to determine whether the neurotoxic effects of apoE4 are mediated by an alteration in calcium homeostasis. For this purpose, effects of recombinant apoE3 and apoE4 on cell viability and intracellular calcium levels were analyzed in a murine hippocampal cell line (HT22) and in primary rat cortical neurons, in the presence or absence of calcium inhibitors. Under basal conditions, apoE4-treated cells displayed increased levels of cytosolic calcium associated with cell death in a dose-dependent manner. Furthermore, apoE4 treatment potentiated the rise in cytosolic calcium and cell death following the administration of a calcium ionophore. The effects of apoE4 on cell viability and calcium homeostasis were inhibited by calcium chelators or by blocking calcium channels, but not by inhibitors of intracellular calcium reserves. Taken together, these results indicate that the neurotoxic effects of apoE4 are dependent on extracellular calcium influx via calcium channels. © 2002 Wiley-Liss, Inc.