Apoptosis and senescence accelerated mice.

摘要

In our present study, we focused on the brain of the senescence accelerated mice (SAM), a novel animal model for aging, in order to investigate the basis for age related loss of function during the normal aging process. The senescence prone P8 strain (SAMP8) was chosen because it demonstrates characteristic neuropathological impairments to the learning and memory pathways. In humans, these are capabilities which are most profoundly affected by aging. The control strain used was age matched senescence resistant R1 strain (SAMR1).; By analyzing the hippocampus of 3 month old adult SAM and 16 month old aged SAM with immunostaining, histochemistry, and western blotting, we found that (1) there were very few TUNEL positive cells in either study group; (2) there were insignificant age related neuronal loss; and (3) none of the pro-apoptotic proteins (caspase-2L, -3, -6, -8, -9, and Bax) were up-regulated with age while the levels of all of the anti-apoptotic proteins (caspase-2S, Bcl-2, and Bcl-XL) remained unchanged with age. This suggests that apoptosis and its accompanying cell loss is a minor event in senescent SAM hippocampus.; Next, we became interested in ascertaining if the low incidence of apoptotic death in the normal aging process of SAM is due to an absence of detrimental external stimuli or an absence of the internal machinery necessary for the cells to carry out apoptosis. To test this hypothesis, we established a novel forebrain ischemia model by occluding the bilateral carotid arteries of the SAM. We found very clear cases of TUNEL positive cells in the pyramidal layer of the hippocampus accompanied by activation of caspase-3 and caspase-9. The activation of caspase-9 in the hippocampus of aged SAMP8 was stronger than that of adult SAMP8 or age-matched SAMR1. This suggests that aged SAMP8 brain cells do undergo apoptosis and may in fact be more vulnerable to ischemia induced apoptosis since it has more significant cleavage of the executioner caspase.; Further studies were also conducted on astrocytes, the largest cell population in the brain which is thought to support the survival of neurons. Using RT-PCR, immunohistochemistry and western blotting, we found that both the protein and mRNA of glial fibrillary acidic protein (GFAP) and the density of GFAP-positive astrocytes in the hippocampus of SAMP8 to be significantly increased during the aging process. However we did not find such an increase in other astrocytic markers, namely glutamine synthetase (GS) and S100 beta. (Abstract shortened by UMI.)