Amano T, Nakanishi H, Oka M, Yamamoto K
Department of Pharmacology, Kyushu University Faculty of Dentistry, Fukuoka, Japan.
Exp Neurol. 1995 Dec;136(2):171-82. doi: 10.1006/exnr.1995.1094.
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.(ABSTRACT TRUNCATED AT 400 WORDS)
衰老加速小鼠（SAM）P8和P10分别随着年龄增长，表现出海绵状变性，尤其是在脑干，以及主要在大脑皮质额叶部分的脑萎缩。为了阐明两种不同的细胞内天冬氨酸蛋白酶，组织蛋白酶E（CE）和D（CD），在这些与年龄相关的病理变化中的作用，研究了这两种酶在SAMP8和P10的脑干和大脑皮质以及抗衰老对照SAMR1四个不同年龄组（1周龄以及2、6和12月龄）中的积累和定位情况。在SAMP8的脑干中，2月龄以上观察到明显的海绵状变性。在年龄匹配的SAMP10的脑干中也观察到相同程度的海绵状变性，但在SAMR1中未观察到。非溶酶体酶CE在所有三个品系1周龄时的脑干中几乎检测不到，但在2月龄时在SAMP8和P10的脑干中显著积累。溶酶体酶CD在所有三个品系1周龄时的脑干中浓度相对较高。在2月龄时，与年龄匹配的SAMR1相比，SAMP8和P10脑干中的CD含量显著增加。在光学显微镜水平上，2月龄SAMP8和P10脑干中CE的免疫反应性增加，见于聚集在海绵状区域的反应性小胶质细胞，而不见于静止或分支形态的小胶质细胞以及星形胶质细胞。CD的免疫反应性增加主要见于反应性星形胶质细胞，部分见于反应性小胶质细胞。免疫印迹分析显示，2月龄SAMP10脑干中的CE仅由42 kDa的成熟形式组成，而该组织中的CD主要由44 kDa的成熟形式及其部分降解产物组成。另一方面，6月龄SAMP10的大脑皮质额叶部分出现明显脑萎缩，而年龄匹配的SAMP8或SAMR1则未出现。尽管在SAMP10萎缩的皮质区域甚至检测不到CE，但所有三个品系大脑皮质中的CD含量都随着衰老略有增加。（摘要截取自400字）
