Age-related progressive neuronal DNA damage associated with cerebral degeneration in a mouse model of accelerated senescence.

The DNA of cerebral neurons in subjects with Alzheimer's disease is extensively damaged, although the morphological features of apoptosis are absent. We investigated whether DNA is damaged in the brains of the SAMP10 strain of mouse, in which accelerated senescence is characterized by age-related cerebral atrophy and cognitive impairment. We performed quantitative terminal deoxynucleotidyl transferase-mediated digoxigenin-labeled dUTP nick end labeling (TUNEL), using paraffin sections. TUNEL positive cells increased in number in the cerebral neurons of SAMP10 mice with aging. TUNEL positive cells were widely distributed in mice at age 13-14 months, and obvious in the olfactory tubercle, anterior cingulate cortex, insular cortex, and amygdala. These TUNEL positive cells did not have the morphological features of apoptosis. Therefore, the DNA became damaged with advancing age through a mechanism other than apoptosis. SAMP10 is a useful mouse model of brain aging that mimics the progressive neuronal DNA damage associated with human neurodegenerative disorders.

Deterioration in learning and memory of inferential tasks for evaluation of transitivity and symmetry in aged SAMP8 mice.

This study examined age-dependent deficits in the learning and memory of inferential tasks, using an established senescence-accelerated mouse model in age-related brain dysfunction (SAMP8) and its genetically related inbred strain (SAMR1). The mice learned two sets of nonspatial odor-odor pairs by association learning successively (i.e., A-->B, X-->Y, then B-->C, Y-->Z). They were tested in transitive inference (i.e., A-->C, X-->Z) and symmetrical inference (i.e., C-->B, Z-->Y). In the probe test of A-->C, X-->Z transitive inference, 1-month-old SAMP8 and control SAMR1 at the same age significantly chose the alternative based on transitive inference, but 4- and 7-month-old SAMP8 performed at a random chance level, in comparison with unambiguous inference by control SAMR1 at the same ages. During the test of C-->B, Z-->Y symmetrical inference, SAMP8 at 1 month of age made errors as frequently as control SAMR1 at the same age, but SAMP8 at 4 and 7 months of age made more errors than SAMR1 at the same ages. At 4 and 7 months of age, SAMP8 made more errors than 1-month-old SAMP8. Control SAMR1 did not show such an age-related deficient. These results indicate that SAMP8 mice have age-related learning and memory deficits in the ability to perform inferential tasks. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in old SAMP8 mice during the performance of inferential tasks mediated by declarative memory.