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The senescence accelerated mouse prone 8 (SAMP8), an animal model of Alzheimer's disease, has amyloid-β deposition in the brain. This study showed that β-secretase activity increased age-dependently in cerebral cortex of SAMP8 and SAMP8's control, SAM resistant/1 (SAMR1), and was higher in the hippocampus of SAMP8 than that of age-matched SAMR1. Cathepsin D activity also increased age-dependently in the cerebral cortex of SAMP8. There was no significant difference between SAMP8 and SAMR1 with regards to activity of cathepsin B. β-secretase activity had a positive correlation with cathepsin D activity in the cerebral cortex of SAMR1 and SAMP8. There was a tendency toward decreased mRNA expression of BACE1, cathepsin D, and cathepsin B in the hippocampus of SAMR1 and SAMP8 with aging. mRNA expression of cathepsin B was elevated significantly in the cerebral cortex of SAMP8 at 2 and 6 months of age compared to that of age-matched SAMR1, and similarly so was cathepsin D at 2 months. This data showed there was no correlation between mRNA expression and activity of β-secretase, cathepsin D, and cathepsin B in the brain of SAMR1 and SAMP8 with age. These findings also indicate it was cathepsin D, not cathepsin B, that contributed to β-secretase activity and the increased amyloid-β production in the SAMP8 brain. In addition, it was necessary to take into account the target selectivity of BACE1 and cathepsin D, not necessary to detect the mRNA expression, when SAMP8 was used as an animal model to determine the effect of β-secretase inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: Vesicular glutamate transporters (VGLUTs), which include VGLUT1, VGLUT2 and VGLUT3, are responsible for the uploading of L-glutamate into synaptic vesicles. The expression pattern of VGLUTs determines the level of synaptic vesicle filling (i.e., glutamate quantal size) and directly influences glutamate receptors and glutamatergic synaptic transmission; thus, VGLUTs may play a key role in learning and memory in the central nervous system. To determine whether VGLUTs contribute to the degeneration or acquisition of learning and memory, we used an animal model for the age-related impairment of learning and memory, senescence-accelerated mouse/prone 8 (SAMP8). KM mice were divided into groups based on their learning and memory performance in a shuttle-box test. The expression of VGLUTs and synaptophysin (Syp) mRNA and protein in the cerebral cortex and hippocampus were investigated with real-time fluorescence quantitative PCR and western blot, respectively. Our results demonstrate that, in the cerebral cortex, protein expression of VGLUT1, VGLUT2, VGLUT3 and Syp was decreased in SAMP8 with age and increased in KM mice, which displayed an enhanced capacity for learning and memory. The protein expression of VGLUT2 and Syp was decreased in the hippocampus of SAMP8 with aging. The expression level of VGLUT1 and VGLUT2 proteins were highest in KM mouse group with a 76–100% avoidance score in the shuttle-box test. These data demonstrate that protein expression of VGLUT1, VGLUT2 and Syp decreases age-dependently in SAMP8 and increases in a learning- and memory-dependent manner in KM mice. Correlation analysis indicated the protein expression of VGLUT1, VGLUT2 and Syp has a positive correlation with the capacity of learning and memory. [Copyright &y& Elsevier]

Abstract: Alzheimer''s disease (AD) is a progressive, neurodegenerative disease, which primarily affects the elderly. Clinical signs of AD are characterized by the neuron loss and cognitive impairment. At gene and protein levels, the senescence-accelerated mouse/prone 8 (SAMP8) is a suitable animal model to investigate the fundamental mechanisms of age-related learning and memory deficits. Huang-Lian-Jie-Du decoction (HL), a well-known traditional Chinese medicinal prescription, has been employed in the treatment of wide range of disease conditions. Modern pharmacological studies have showed that HL possesses many effects, which include amelioration of learning and memory function of CNS. This paper investigated the gene expression patterns of hippocampus and cerebral cortex of SAMP8, which were treated with HL employing the cDNA microarray and real time quantitative RT-PCR techniques. The results showed that HL has the significant modulating effects on age-related changes of the gene expressions in the hippocampus and cerebral cortex in SAMP8, which include genes that involved in signal transduction (Dusp12, Rps6ka1, Rab26, Penk1, Nope, Leng8, Syde1, Phb, Def8, Ihpk1, Tac2, Pik3c2a), protein metabolism (Ttc3, Amfr, Prr6, Ube2d2), cell growth and development (Ngrn, Anln, Dip3b, Acrbp), nucleic acid metabolism (Fhit, Itm2c, Cstf2t, Ddx3x, Ercc5, Pcgfr6), energy metabolism (Stub1, Uqcr, Nsf), immune response (C1qb), regulation of transcription (D1ertd161e, Gcn5l2, Ssu72), transporter (Slc17a7, mt-Co1), nervous system development (Trim3), neurogila cell differentiation (Tspan2) and 24 genes whose biological function and process were still unknown. It was suggested by the changes of the 62 genes with HL treatment that the ameliorating effect of HL on the cognitive impairments of SAMP8 might be achieved by multi-mechanism and multi-targets. [Copyright &y& Elsevier]

Abstract: Increasing evidences have indicated that STUB1 may be closely linked to Alzheimer''s disease (AD). Senescence-accelerated mice (SAM) prone/8 (SAMP8) is a generally acknowledged animal model for senescence and AD, and SAM resistant/1 (SAMR1) is its control. In this study, we investigated the detailed expression of STUB1 in the brain of SAMP8 with aging and its responses to five anti-AD traditional Chinese medicinal (TCM), using real-time fluorescence quantitative PCR and Western blot technique. Results showed that with the aging process, both mRNA and protein expression of STUB1 in the cerebral cortex and hippocampus from SAMR1 increased after 2 months, while they decreased in brain tissues from SAMP8 after 6 months. Compared with SAMR1, the mRNA and protein expression of STUB1 decreased after 10 months in SAMP8 but could be up-regulated by the five anti-AD TCM used in this study. These results indicated that the expression of STUB1 in the brain of SAMP8 was abnormal and this abnormality could be reversed by anti-AD TCM. The data suggested that a deficiency in STUB1 may lead to a reduction in aberrant protein scavenging, causing abnormal protein accumulation in the brain of SAMP8. Thus, STUB1 might be a potential target for anti-AD TCM. [Copyright &y& Elsevier]

Abstract: The senescence-accelerated mouse (SAM) is an animal model for studying senescence and age-associated disorders due to its inherited aging phenotype. The SAM/prone8 (SAMP8) is a useful animal model to investigate the fundamental mechanisms involved in age-related learning and memory deficits that may have relevance to age-associated AD, while SAM/resistant1 (SAMR1) shows normal. To identify genes rendering the cognitive deterioration with aging, the subtractive cDNA libraries containing 1924 clones with the positive ratio of 96.18% were generated and the microarray containing 3136 cDNA was prepared. The results of screening libraries by the microarray showed that of all 91 differentially expressed genes, 50 were over-expressed and 41 were low-expressed in SAMP8. Some of the identified genes were confirmed by the real time quantitative RT-PCR. These results indicated the profiles of gene expression in the hippocampus of SAMP8 and SAMR1 were significantly different, which may play important roles in the age-related cognitive deficit in SAMP8, suggesting those genes related to the cognitive deficient or pathology change in the brain of SAMP8 may be potential gene targets for Alzheimer''s disease therapy. [Copyright &y& Elsevier]