Bi Xiaoning, Head Elizabeth, Cotman Carl W, Lynch Gary
Department of Psychiatry and Human Behavior, University of California at Irvine, Irvine, California 92697, USA.
J Comp Neurol. 2003 Sep 22;464(3):371-81. doi: 10.1002/cne.10795.
Elevated levels of the lysosomal enzyme cathepsin D are found in the early stages of Alzheimer's disease (AD) and co-occur with intraneuronal tangles. The present study tested whether increases in cathepsin D would emerge during aging in another mammalian species. Regional brain patterns of cathepsin D immunostaining were compared in dogs ages 0.35 to 16 years. Accumulations of immunopositive material were evident in neuronal cell bodies in many forebrain sites in middle-age to old dogs (>/=6 years). Three types could be distinguished: (1) dense aggregates with no particular position within the cell body; (2) crescent-shaped "caps" that occupied one pole of the cell body; and (3) very dense "spikes" that extended from the cell body for variable distances into the apical dendrite; these spikes were found in only a few areas, most notably the subiculum and layer V of neocortex. The spikes appeared between ages 2 and 5 years and increased steadily with age thereafter. Spikes were found in the subiculum in the aged human brain but only infrequently; they were, however, present in large numbers in AD brains. These results established that brain aging in dogs is (1) well advanced by middle age, (2) varies markedly across regions, and (3) in at least some of its aspects (dystrophic dendrites) is prominent in areas known to exhibit pathology early in the course of AD. Combined with previous results for rats, these findings indicated that changes in cathepsin D observed in AD, in particular in the temporal lobe, reflect a generalized mammalian pattern of brain aging.
在阿尔茨海默病（AD）早期阶段可发现溶酶体酶组织蛋白酶D水平升高，且与神经元内缠结同时出现。本研究检测了在另一种哺乳动物衰老过程中组织蛋白酶D水平是否会升高。比较了0.35至16岁犬类大脑中组织蛋白酶D免疫染色的区域模式。在中年至老年犬（≥6岁）的许多前脑部位，神经元细胞体中可见免疫阳性物质的积累。可区分出三种类型：（1）在细胞体内无特定位置的致密聚集体；（2）占据细胞体一极的新月形“帽”；（3）从细胞体延伸到顶端树突不同距离的非常致密的“尖刺”；这些尖刺仅在少数区域发现，最显著的是海马下托和新皮质第V层。尖刺在2至5岁之间出现，此后随年龄稳步增加。在老年人类大脑的海马下托中偶尔能发现尖刺；然而，它们在AD大脑中大量存在。这些结果表明，犬类大脑衰老：（1）在中年时已相当明显；（2）在不同区域有显著差异；（3）至少在某些方面（营养不良性树突）在AD病程早期已知有病变的区域较为突出。结合之前对大鼠的研究结果，这些发现表明在AD中观察到的组织蛋白酶D变化，特别是在颞叶，反映了哺乳动物大脑衰老的普遍模式。
