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Abstract: The purpose of this study was to elucidate the alteration of catecholamine metabolism and the contribution of catecholamines to the decline of learning and memory in the brain of the senescence-accelerated mouse prone 10 (SAMP10) with aging. Catecholamines and their metabolites in the cerebral cortex were measured by HPLC-ECD. The protein levels of tyrosine hydroxylase (TH) as well as TH phosphorylated at Ser19 or Ser40, dopamine-β-hydroxylase (DβH), and cAMP-dependent protein kinase (PKA) were determined by western blot analysis. Dopamine (DA) and norepinephrine (NE) levels in SAMP10 were significantly lower than those in control animals. However, no significant difference was observed in catecholamine metabolite levels between SAMP10 and control mice. The level of TH phosphorylation at Ser40 in SAMP10 was significantly lower than that in control mice, but no significant difference was observed in the levels of TH, TH phosphorylated at Ser19, or DβH. The amount of PKA, which regulates the phosphorylation of TH at Ser40, was significantly lower in SAMP10 than in control mice. The present study demonstrated that a decline in DA and NE concentrations was observed in the cerebral cortex of SAMP10 with aging, and this decrease of catecholamine levels was caused by impairment of their synthetic pathway. These impairments are considered to be caused by downregulation of TH phosphorylation at Ser40 as a result of PKA deficiency. The present study suggests that the decline of learning and memory abilities of SAMP10 is caused by a decrease in catecholamine synthesis in the cerebral cortex with aging. [Copyright &y& Elsevier]

Abstract: To investigate the effect of a high-fat diet on brain and pancreas functions, we used SAMP10 mice that have characteristics of brain atrophy and cognitive dysfunction with aging. Simultaneously, we investigated the effect of green tea catechin consumption on high-fat diet feeding, because green tea catechin has been reported to improve brain atrophy, brain dysfunction and obesity. The body weight of mice fed a high-fat diet from 2 to 12 months was higher than that of the control, although the calorie intake was not. The high-fat diet also increased insulin secretion; however, the hypersecretion of insulin and obesity were suppressed when mice were fed a high-fat diet with green tea catechin and caffeine. Furthermore, brain atrophy was suppressed and the working memory, tested using Y-maze, improved in mice fed a high-fat diet containing green tea catechin and caffeine. The secretion of insulin might affect both obesity and brain function. A strong correlation was found between working memory and insulin release in mice fed a high-fat diet with green tea catechin and/or caffeine. The results indicate the protective effect of green tea catechin and caffeine on the functions of brain and pancreas in mice fed a high-fat diet. [Copyright &y& Elsevier]

Green tea catechins (GT-catechins) have been reported to have an antioxidative effect. We investigated the effect of long-term GT-catechin intake on aging and oxidative damage using aged mice with accelerated senescence (SAMP10), a model of brain senescence with cerebral atrophy and cognitive dysfunction. Major atrophy was observed in the rhinencephalon, hippocampus and striatum of 12-month-old untreated SAMP10 mice. Similarly, levels of 8-oxodeoxyguanosine (8-oxodG), a marker of oxidative DNA damage, were higher in these parts of the cerebrum than in the cerebral cortex and liver. GT-catechin intake effectively suppressed such atrophy in 12-month-old SAMP10 mice. A preventive effect of GT-catechin intake on oxidative DNA damage was also observed in the rhinencephalon (an area particularly susceptible to atrophy) at 6 months of age, i.e. during the early stages of atrophy. A suppressive effect of GT-catechin intake on cognitive dysfunction, as determined by the learning time needed to acquire an avoidance response and assessments of working memory in a Y-maze, was also found in 12-month-old mice. These results suggest that GT-catechin intake partially improves the morphologic and functional alterations that occur naturally in the brains of aged SAMP10 mice. [Copyright &y& Elsevier]

Learning and memory functions decline with aging. Oxidative damage has been considered to be a cause of age-associated brain dysfunction because the brain is believed to be particularly vulnerable to oxidative stress. We investigated the influence of green tea catechins (GT-catechin), which have been reported to have antioxidative effects, on learning and memory using senescence-accelerated mice (SAMP10). The learning time for acquisition of avoidance response and the ratio of working memory in a Y-maze indicated that GT-catechin intake was effective for improvement of learning and memory functions in aged SAMP10 mice. In addition, we found that GT-catechin intake was effective for the suppression of cerebral atrophy in SAMP10 of 12-month-old mice. Levels of 8-oxodeoxyguanosine (8-oxodG) were suppressed in rhinencephalon and in liver of SAMP10 mice that had drunk catechin water. These results suggest that intake of GT-catechin over a long term partially improves oxidative damage and morphologic and functional alterations of the brain in aged SAMP10. [Copyright &y& Elsevier]

In order to explore the pathogenic mechanisms of cerebral senescence and its possible effective acupuncture therapy, we applied cDNA array technique to study expression of the aging-related genes in hippocampus and acupuncture effect on them. SAMP10 and SAMR1 were selected and randomly divided into four groups: R1 control group, P10 control group, P10 acupuncture group and P10 pseudo-acupuncture group. The results showed that acupuncture not only could partly or completely reverse the effect of aging on hippocampal gene expression, but also influence some gene expression which were unrelated to aging. However, pseudo-acupuncture had some effect on aging-unrelated gene expression and little or no effect on aging-related genes. Therefore, we suspect that acupuncture points may have both therapeutic effect and “stress-inducing reaction”. Pseudo-acupuncture has only “responsiveness” without therapeutic effect. [Copyright &y& Elsevier]

We studied age-related behavioral changes in senescence-accelerated P10/Ta mice (SAMP10) reared under specific pathogen-free (SPF) conditions. Unlike SAMP8/Ta (SAMP8), the SAMP10 did not exhibit low anxiety-like behavior in the plus-maze test and the impairment of the passive avoidance task of SAMP10 was milder than that of SAMP8. SAMP10 showed more age-related abnormal behavior than did SAMP8, such as a decrease in shock sensitivity, increases in the duration of immobility during the tail suspension and the forced swimming tests and a decrease in swimming speed in a water maze task. SAMP10 showed a significant decrease in dopamine content in the anterior cortex. Furthermore, the behavioral depression observed in SAMP10 was ameliorated by dopaminergic stimulants such as apomorphine and a sustained release formulation of thyrotropin-releasing hormone (TRH-SR), at doses having no significant effects on spontaneous motor activity. These findings suggest that the dopaminergic function may contribute to behavioral depression. The present results indicate that SAMP10 shows a greater age-related decrease in the responsiveness to averse or stressful stimuli than do the R1 and P8 strains, which suggests that SAMP10 may be a useful animal model of age-related behavioral depression or decrease in spontaneity. [Copyright &y& Elsevier]

Objective: SAMP10 is senescence accelerated mouse with character of brain atrophy and deficit in learning and memory compared with SAMR1, its homologous normal aging mouse. Thus, we applied the model mouse to study the age-related changes in telomere of brain cell. Method: The Southern hybridization was taken to measure the changes in telomere of brain cell in different month-age of SAMR1 and SAMP10. Result: The telomere length of SAM was found to reach to 17–25 kb and showed a decreasing trend with aging in brain cell of SAMP10. Conclusion: As the changes in telomere of brain cell of SAMP10 shown, the shortening of cell telomere has a remarkable correlation to senility. [Copyright &y& Elsevier]

The senescence-accelerated mouse (SAMP8) showed age-related deficits in avoidance and spatial learning tasks, and also exhibited reduced anxiety-like behavior in tests involving food neophobia, an elevated plus-maze and punished water-licking. The emotional change in SAMP8 was considered to be closely related to the deficits in the learning tasks. Aged SAMR1 showed similar behavioral changes to those in SAMP8 mice, indicating that some of the behavioral changes in SAMP8 may be derived from accelerated aging. SAMP10 mice also showed learning impairment in the avoidance tasks, although the impairment was less than that in SAMP8 mice. SAMP10 exhibited marked behavioral depression when subjected to a tail suspension test or forced swimming test. Thus, the SAMP10 strain may be useful for studying age-related behavioral depression and reduced spontaneity. SAMP8 and SAMP10 also exhibited marked disruption of the circadian rhythms of spontaneous motor activity (SMA) and drinking behavior, and bright light stimulation ameliorated the abnormal circadian rhythms in SAMP8. These findings suggest that SAMP8 and SAMP10 are also valid animal models for age-related disorders of learning and memory, emotional behavior and circadian rhythms in elderly humans and in those with senile dementia. [Copyright &y& Elsevier]

We found a significant elevation in the IL-1β mRNA content in the hippocampus of SAMP8 in comparison with that of SAMR1 at 10 months after birth. In both senescence-accelerated mouse (SAM) strains, the increases in brain IL-1β protein were more noticeable at 10 months than at 2 or 5 months. The only differences found in protein levels between strains were at 10 months and consisted of elevations in TNFα and IL-6 in the cerebral cortex and the hippocampus as well as in IL-1β in the hippocampus and the hypothalamus, as compared with SAMR1. The increases in expression of these proinflammatory cytokines in the brain seem to be involved in the age-related neuronal dysfunction and/or learning deficiency in SAMP8. With regard to SAMP10, we performed behavioral and neurochemical studies and found evidence of depression in both tail suspension and forced swimming tests as well as an increase in D2 dopamine receptors and 5-HT1A receptors in the cortex and the midbrain at 7 months in SAMP10, suggesting that the SAMP10 strain provides a useful model of age-associated depression. We also report that a reduction of muscarinic acetylcholine receptors and protein kinase C in the brain could underlie learning dysfunction in SAMP10. [Copyright &y& Elsevier]