β-Amyloid_(1–40)-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase

Abstract 

β-Amyloid_(1–40)-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase. β-Amyloid protein is thought to contribute to the pathophysiology of Alzheimer’s disease by inducing neuronal apoptosis. Our previous work has demonstrated that β-amyloid activates voltage-dependent Ca²⁺ channels in the cortex, resulting in an increase in intracellular Ca²⁺ concentration. Calpain is a Ca²⁺-dependent neutral protease which becomes activated following alterations in intracellular Ca²⁺ homeostasis. In this study we have demonstrated that β-amyloid increases calpain activity in cultured cortical neurones in a time-dependent manner. Use of the cell-permeable calpain inhibitor, MDL 28170, has identified cleavage of the DNA-repair enzyme, poly-ADP-ribose polymerase, and DNA fragmentation as downstream consequences of calpain activation. Thus, we propose that the stimulatory effect of β-amyloid on Ca²⁺ influx triggers calpain-mediated DNA fragmentation in cultured cortical neurones.

Keywords:  β-Amyloid, Calpain, Poly-ADP-ribose polymerase, Apoptosis