Phenanthroline impairs βAPP processing and expression, increases p53 protein levels and induces cell cycle arrest in...

Mis-functional βAPP processing is deemed to be the major phenomenon resulting in increased neuronal cell death, impaired neurogenesis and the loss of synapses, which eventually manifest as the complex symptoms of Alzheimer's disease. Despite of several milestones having been achieved in the field of drug development, the stigma of the disorder as an incurable disease still remains. Some ADAM proteases mediate the physiological non-amyloidogenic α-secretase processing of βAPP that generates neuroprotective sAPPα production. Earlier studies have also pointed out the role of p53 in Alzheimer's disease neuropathology, although a direct link with metalloprotease activities remains to be established. In this study, we explored the consequences of α-secretase inhibition on p53 status in cultured human neuroblastoma SH-SY5Y cells by means of specific inhibitors of ADAM10 and ADAM17 and the metal chelator and general metalloprotease inhibitor phenanthroline. We establish that, beyond the ability of all inhibitors to affect sAPPα production to varying degrees, phenanthroline specifically and dose-dependently lessened βAPP expression, a phenomenon that correlated with a strong increase in p53 protein levels and a concomitant decrease of the p53-degrading calpain protease. Furthermore, treatment of cells at concentrations of phenanthroline similar to those inducing increased levels of p53 induced cell cycle arrest leading to apoptosis. Altogether, our results identify new roles of phenanthroline in perturbing βAPP, p53 and calpain biology, and suggest that the use of this compound and its derivatives as antimicrobial and anti-cancer therapies might trigger Alzheimer's disease pathogenesis.