Abeta-mediated activation of the apoptotic cascade in cultured cortical neurones: a role for cathepsin-L.
Deposition of beta-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 Abeta 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 6 h following beta-amyloid treatment. The proclivity of beta-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, beta-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 beta-amyloid-induced apoptosis. Thus, the results from this study demonstrate that beta-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.
Boland
Barry
B
Department of Physiology, Trinity College Neuroscience Institute, Trinity College, Dublin 2, Ireland.
Campbell
Veronica
V
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D003546:Cysteine Endopeptidases; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D011065:Poly(ADP-ribose) Polymerases; D002403:Cathepsins; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534280:Ctsl protein, rat