Amyloid β (Aβ) peptide is a critical causative factor in Alzheimer's disease (AD) and of a variety of fragmented Aβ peptides Aβ1-42 thought to exhibit the most neurotoxic effect. The present study investigated the effects of Fe3+ on Aβ1-42 internalization and Aβ1-42-induced caspase activation and neurotoxicity using mouse hippocampal slices and cultured PC-12 cells. Extracellularly applied Aβ1-42 increased the cell-associated Aβ1-42 levels in a concentration-dependent manner, and the effect was enhanced by adding Fe3+. Fe3+-induced enhancement of the cell-associated Aβ1-42 levels was significantly inhibited by the endocytosis inhibitors dynasore and methyl-β-cyclodextrin. Aβ1-42 reduced PC-12 cell viability in a concentration-dependent manner, and further reduction of the cell viability was obtained with Fe3+. Aβ1-42-induced reduction of cell viability was not affected by A187, an antagonist of amylin-3 receptor. Aβ1-42 activated caspase-3, caspase-4, and caspase-8 to a variety of degrees and Fe3+ further enhanced Aβ1-42-induced activation of caspase-3 and caspase-4. Taken together, these results indicate that Fe3+ accelerates endocytic internalization of extracellular Aβ1-42, enhances Aβ1-42-induced caspase-3/caspase-4 activation, and promotes Aβ1-42-induced neuronal cell death, regardless of amylin receptor.
Keywords: Amyloid β1–42; Caspase activation; Endocytosis; Fe3+; Internalization; Neuronal cell death.