Aβ-mediated activation of the apoptotic cascade in cultured cortical neurones: A role for cathepsin-L

Deposition of β-amyloid protein in the brain is a neuropathological hallmark of Alzheimer's disease. An additional feature of this disease is an upregulation of the lysosomal system, however, the role of lysosomal proteins in the pathogenesis of this neurodegenerative condition is unclear. In this study, we demonstrate that Aβ increases activity of the lysosomal protease, cathepsin-L, and promotes a transient increase in cytosolic expression of cathepsin-L in cultured cortical neurones. The increase in cathepsin-L activity and concentration in the cytosol is evident 6h following β-amyloid treatment. The proclivity of β-amyloid to induce apoptotic changes, such as activation of caspase-3, cleavage of the DNA repair enzyme, poly-ADP ribose polymerase, and DNA fragmentation, were prevented by the selective cathepsin-L inhibitor Z-FF-FMK. In contrast, β-amyloid had no effect on expression levels or cellular distribution of cathepsin-D and the cathepsin-D inhibitor peptide failed to protect cortical neurones from β-amyloid-induced apoptosis. Thus, the results from this study demonstrate that β-amyloid impacts on cathepsin-L as an upstream event in the neurodegenerative process and this result highlights the potential role of lysosomal components in the pathogenesis of Alzheimer's disease.