Genistein ameliorates β-amyloid peptide (25–35)-induced hippocampal neuronal apoptosis

β-Amyloid protein (Aβ), a major component of senile plaques of Alzheimerʹs disease (AD) brain, causes elevation of the intracellular free Ca2+ level and the production of robust free radicals, both of which contribute greatly to the AD-associated cascade including severe neuronal loss in the hippocampus. Genistein, the most active molecule of soy isoflavones, protects diverse kinds of cells from damage caused by a variety of toxic stimuli. In the present study, we investigated the neuroprotective effect of genistein against Aβ25–35-induced apoptosis in cultured hippocampal neurons, as well as the underlying mechanism. Aβ25–35-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, is associated with an increase in intracellular free Ca2+ level, the accumulation of reactive oxygen species (ROS), and the activation of caspase-3. All these phenotypes induced by Aβ25–35 are reversed by genistein. Our results further show that at the nanomolar (100 nM) level, genistein protects neurons from Aβ25–35-induced damage largely via the estrogen receptor-mediated pathway, and at the micromolar (40 μM) level, the neuroprotective effect of genistein is mediated mainly by its antioxidative properties. Our data suggest that genistein attenuates neuronal apoptosis induced by Aβ25–35 via various mechanisms.