Neurotoxic mechanisms triggered by ß-amyloid: Role of oxidative stress, caspases and JNK pathway

Evidence is provided that increased oxidative stress might play a crucial role in the rapid progression in familial Alzheimer’s disease bearing the Swedish APP mutation (APPsw).

Here we investigated the effect of APPsw on oxidative stress-induced cell death mechanisms in PC12 cells (1). The activity of the executer caspase-3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation was significantly increased. This elevated activity is the result of the enhanced activation of both, intrinsic and extrinsic apoptosis pathway including activation of caspase-2 and caspase-8. We also observed an enhanced activation of JNK pathway and an attenuation of apoptosis by inhibition of JNK, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in FAD patients could be a consequence of an increased vulnerability of neurons through activation of different apoptotic pathways as consequence of elevated oxidative stress levels.

1. Marques et al. J Biol Chem (2003) in press

Support contributed by: the Deutsche Forschungsgemeinschaft, the Alzheimer Forschung Initiative and Dr. Robert Pfleger-Stiftung