Mini reviewThe senescence-accelerated prone mouse (SAMP8): A model of age-related cognitive decline with relevance to alterations of the gene expression and protein abnormalities in Alzheimer's disease
Introduction
The senescence-accelerated mouse (SAM) is a model of accelerated senescence that was established through phenotypic selection from a common genetic pool of AKR/J strain of mice (Takeda et al., 1981). In 1975, certain littermates of AKR/J mice were noticed to become senile at an early age and had a shorter life span. Five of these litters with early senescence were selected as the progenitors of the senescence-accelerated-prone mice (SAMP). Three litters with normal aging process were also selected as the progenitors of senescence-accelerated-resistant mice (SAMR) (Takeda et al., 1981, Miyamoto, 1997). Thereafter, selective inbreeding was applied based on the degree of senescence, the lifespan, and the age-associated pathologic phenotypes (Hosokawa et al., 1997). In 1981, the SAM model was established, including nine major SAMP substrains and three major SAMR substrains, each of which exhibits characteristic disorders. The characteristics of the SAMP substrains are summarized in Table 1. It should be noted that other strains were also derived from these major substrains (Takeda, 1999).
Recently, SAMP8 mice have drawn attention in gerontological research of dementia due to its characteristic learning and memory deficits at old age (Flood and Morley, 1998). The life span of ARK/J mice is approximately 10 months. Depending on the microbiological condition of housing, the life span of SAMP8 mice ranges from 10 months to 17 months. Such life span is shorter than that of SAMR1, which ranges from 19 months to 21 months (Flood and Morley, 1998). The unique characteristic of SAMP8 mice is that it has low incidence of other phenotypic aging alterations when its deficits in learning and memory are developed (Flood and Morley, 1998). Therefore, it is a good rodent model for cognitive impairment in aged subjects. Moreover, in comparison with aged SAMR1 mice, the aged SAMP8 mice show impairments in learning tasks, altered emotion, abnormality of circadian rhythm (Miyamoto, 1997), and increased oxidative stress (Butterfield et al., 1997). When compared to young SAMP8, aged SAMP8 mice also show clear age-related impairment in learning assessed by foot shock avoidance (Flood and Morley, 1993), which correlates with oxidative stress parameters (Farr et al., 2003). These findings are consistent with the free radical theory of aging that posits the oxidative modification by reactive oxidative species (ROS) on biomolecules contribute to the cellular dysfunction in aging (Harman, 1956).
Different paradigms were used to improve the age-related learning and memory deficits in aged SAMP8 mice (Farr et al., 2003, Kumar et al., 2000, Morley et al., 2002, Yasui et al., 2002). These studies not only suggest potential therapeutics for age-related dementia, but they also provide insight into the mechanism underlying the learning and memory deficits observed in aged SAMP8 mice. For example, treating aged SAMP8 mice with antioxidants decreased oxidative stress in aged SAMP8 brain and improved their learning and memory, indicating that oxidative stress contributes to the impairment of learning and memory observed in the SAMP8 mice (Butterfield et al., 1997, Farr et al., 2003, Yasui et al., 2002, Okatani et al., 2002). Moreover, evidence strongly suggests that abnormal expression of amyloid-β (Aβ) contributes to the cognitive decline in the aged SAMP8 mice, since reduction of Aβ by antibody or antisense oligonucleotides reduce oxidative stress and improve learning and memory deficits in aged SAMP8 mice (Kumar et al., 2000, Morley et al., 2002, Morley et al., 2000, Poon et al., 2004d). These studies suggest that SAMP8 not only is a good model for studying age-related learning and memory deficits, but may also prove to be a useful model for studying Aβ-mediated effects in cognitive decline. Of course, the latter effects have relevance to Alzheimer's Disease (AD).
Many reports provide insights into the mechanism of the cognitive impairment in SAMP8 mice. The neurochemical alterations and pathological changes in SAMP8 were previously reviewed (Takeda, 1999, Flood and Morley, 1998, Morley et al., 2001). Therefore, it is the intent of this article to review the recent findings on alteration of gene expression and protein abnormalities that are relevant to age-related learning and memory deficits in SAMP8 mice brain.
Section snippets
Gene expression alterations in SAMP8 mice
Cross breeding of a CD-1 dame and a SAMP8 sire developed a series of paternal backcross strains. Siblings from each backcross were then bred to establish strains with different percentages of SAMP8 genes. It was demonstrated that the age-related learning and memory impairment is correlated to the percentage of SAMP8 genes (Morley et al., 2001). Initial examination of the genetic profiles revealed that at least one genotype in SAMP8 strain is different from that in the AKR/J strain (Takeda, 1999
Neuroprotection/ROS production
One of the direct results of increased APP gene expression in the SAMP8 mice brain is the increased level of Aβ level (Poon et al., 2004). As noted above, using antisense or antibody to reduce the level of Aβ in SAMP8 improved cognitive function and reduced oxidative stress in SAMP8 mice brain, suggesting that the increased Aβ level in brain contributes to the CNS dysfunction in SAMP8 mice (Kumar et al., 2000, Poon et al., 2004d, Poon et al., 2005a). Moreover, a peripheral antibody prevents the
Conclusion
This mini-review summarizes current findings of altered gene expression and abnormal proteins in SAMP8 mice brain. The genes and proteins described in this review are functionally categorized into neuroprotection, signal transduction, protein folding/degradation, cytoskeleton and transport, immune response and ROS production. All of these processes are reportedly involved in age-related cognitive decline (Butterfield and Stadtman, 1997, Poon et al., 2004a, Poon et al., 2004b, Lal and Forster,
Acknowledgements
This work was supported in part by grants from the National Institutes of Health to D. A. Butterfield (AG-10836; AG-05119).
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