Amyloid β (Aβ) peptide is a critical causative factor in Alzheimer's disease (AD) and of a variety of fragmented Aβ peptides Aβ thought to exhibit the most neurotoxic effect. The present study investigated the effects of Fe on Aβ internalization and Aβ-induced caspase activation and neurotoxicity using mouse hippocampal slices and cultured PC-12 cells. Extracellularly applied Aβ increased the cell-associated Aβ levels in a concentration-dependent manner, and the effect was enhanced by adding Fe. Fe-induced enhancement of the cell-associated Aβ levels was significantly inhibited by the endocytosis inhibitors dynasore and methyl-β-cyclodextrin. Aβ reduced PC-12 cell viability in a concentration-dependent manner, and further reduction of the cell viability was obtained with Fe. Aβ-induced reduction of cell viability was not affected by A187, an antagonist of amylin-3 receptor. Aβ activated caspase-3, caspase-4, and caspase-8 to a variety of degrees and Fe further enhanced Aβ-induced activation of caspase-3 and caspase-4. Taken together, these results indicate that Fe accelerates endocytic internalization of extracellular Aβ, enhances Aβ-induced caspase-3/caspase-4 activation, and promotes Aβ-induced neuronal cell death, regardless of amylin receptor.