| Research Abstract |
In past years attention has been paid to the altered intracellular proteolytic system in relation to different neuropathological conditions, In this study, we have determined the association of the proteolytic events relating to cathepsin E, a non-lysosomal aspartic proteinase, with various neuronal degeneration process. First, age-related changes in the expression and localization of cathepsin E was determined in the rat cerebral cortex and the brainstem. The enzyme was barely detectable in these tissues in the embryonic stages, whereas it was increasingly expressed in these tissues with aging after birth. cathepsin E was colocalized with the lysosomal aspartic proteinase cathepsin E in the lipofuscin-containing lysosomes in the aged neurons. The results indicate that aging results in the increased expression and localization of cathepsin E in neurons and changes in the endosomal/lysosomal proteolytic system, which may be related to lipofucigenesis. Second, cathepsin B was shown to be
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the most abundant in microglia among various brain cell types, where the enzyme existed predominantly as the mature enzyme in the endosome. Third, we have examined effects of Bcl-2 overexpression on selective neuronal death of the hippocampal CA1 neurons and the dentate granule cells induced by hypoxic-ischemia in adult transgenic mice overexpressing human Bcl-2 under the control of neuron-specific enolase. The results indicate that the overexpression of Bcl-2 effectively suppressed dentate granule cell apoptosis but only delayed cell death of the CA1 neurons, suggesting the occurrence of non-apoptiotic, caspase-independent mechanism for neuronal death in the CA1 subfield. Fourth, when treated with activated microglia, neuronal PC12 cells undergo apoptosis accompanied by caspase-3-like protease activation and DNA fragmentation. Pretreatment of the neuronal cells with caspase-3-like protease inhibitors did not reverse this cell death. Bcl-2 overexpression also could not suppress the activated microglia-induced neuronal death. this study provides an alternative death pathway for activated microglia- induced neuronal death by blockage of the caspase-3 protease cascade. Less
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