Up-regulation of the lysosomal system in experimental models of neuronal injury: Implications for Alzheimer's disease

Previous studies established that the populations of neurons that frequentl y degenerate in Alzheimer's disease exhibit robust up-regulation of the lys osomal system. In this study, we investigated alterations of the lysosomal system during different forms of experimental injury in rat hippocampal neu rons in culture, utilizing a combination of immunocytochemical and biochemi cal methods. Using triple-label immnocytochemistry for activated caspase-3, fragmentation of DNA and the microtubule-associated protein-2, we characte rized treatment paradigms as models of the apoptotic (staurosporine, campto thecin), the oncotic (high-dose menadione, glutamate), and the mixed apopto tic and oncotic (low-dose menadione) pathways of neuronal death. Slowly dev eloping apoptotic or slowly developing mixed apoptotic and oncotic forms of neuronal injury were associated with substantial increases in the number a nd size of cathepsin D-positive vesicles (late endosomes and mature lysosom es) as determined by immunocytochemistry, and elevated levels of cathepsin D by western blotting. In agreement with our previous findings in Alzheimer 's disease, where lysosomal system activation was not restricted to overtly degenerating neurons, up-regulation of this system was also detected quite early during the course of experimental neuronal injury, preceding the dev elopment of dystrophic neurites, nuclear segmentation or fragmentation of D NA. These findings implicate lysosomal system activation, both in Alzheimer's d isease and in experimental models of neuronal injury, as an important event associated with early stages of neurodegeneration. (C) 2000 IBRO. Publishe d by Elsevier Science Ltd. All rights reserved.