A role for p53 in the β-amyloid-mediated regulation of the lysosomal system

Abstract 

β-Amyloid accumulates around neurons in Alzheimer's disease and is thought to contribute to the neurodegenerative process. This study examined the role of the tumour suppressor protein, p53, in the neurodegenerative pathway, with focus on the interaction of p53 with the lysosomal system. β-Amyloid increased expression of p53 and its transcription target, Bax, in cultured cortical neurons. In addition, Aβ increased the association of phospho-p53^ser15 with the lysosomal compartment and this correlated with destabilization of the lysosomal membrane and a concomitant increase in cytosolic cathepsin-L activity. These effects of β-amyloid were abolished by the p53 inhibitor, pifithrin-α, and siRNA-mediated knockdown of p53, demonstrating that p53 is a critical regulator of lysosomal integrity and the induction of cathepsin-L protease activity. In addition, activation of the apoptotic cascade was abolished by pifithrin-α. We conclude that p53 associates with the lysosome to regulate a lysosomal branch of the apoptotic cascade which contributes to β-amyloid-mediated neurodegeneration.

Keywords: β-Amyloid, Lysosome, p53, Apoptosis