Senescence-accelerated mouse (SAM) P8 and P10 exhibit a spongy degeneration, especially in the brain stem, and a brain atrophy mainly in the frontal portion of the cerebral cortex, respectively, with advancing age. In an attempt to clarify the role of two distinct intracellular aspartic proteinases, cathepsins E (CE) and D (CD), in these age-related pathological changes, accumulation and localization of these enzymes were investigated in the brain stem and the cerebral cortex of SAMP8 and P10 and in the senescence-resistant control SAMR1 with four different age groups (1 week and 2, 6, and 12 months). In the brain stem of SAMP8, a marked spongy degeneration was observed at more than 2 months of age. The same degree of spongy degeneration was also observed in the brain stem of age-matched SAMP10 but not SAMR1. The nonlysosomal enzyme CE was barely detectable in the brain stem of all three strains at 1 week of age, but it was markedly accumulated in the brain stem of SAMP8 and P10 at 2 months of age. The lysosomal enzyme CD was found in relatively high concentration in the brain stem of all three strains at 1 week of age. At 2 months of age, CD contents were significantly increased in the brain stem of SAMP8 and P10 compared with those of age-matched SAMR1. At the light-microscopic level, increased immunoreactivities for CE in the brain stem of 2-month-old SAMP8 and P10 were found in reactive microglial cells clustered at the spongy areas but not in microglial cells with resting or ramified morphology and astrocytes. The increased immunoreactivity for CD was observed mainly in reactive astrocytes and partially in reactive microglial cells. Immunoblotting analyses revealed that CE in the brain stem of 2-month-old SAMP10 consisted of only the mature form of 42 kDa, whereas CD in this tissue is composed of mainly the mature form of 44 kDa and partially its degradation products. On the other hand, there was a marked brain atrophy mainly in the frontal portion of the cerebral cortex of 6-month-old SAMP10 but not in age-matched SAMP8 or SAMR1. Although CE was not detectable even in the atrophied cortical area of SAMP10, CD contents in the cerebral cortex slightly increased with senescence in all three strains. These results strongly suggest that CE and CD are upregulated in reactive glial cells and are closely linked with the progression of the spongiform degeneration in the brain stem of SAMP8 and P10, but not in the atrophy developed in the cerebral cortex of SAMP10.
All Science Journal Classification (ASJC) codes
- Developmental Neuroscience