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Highlights: [•] This review focuses on the behavioral and histopathological signature of AD in SAMP8 mice. [•] The behavioral and pathological features detected by the different methods in SAMP8 mice at different ages were listed. [•] The preclinical trials of potential therapeutic modalities using SAMP8 mice were summarized. [•] We compared the merits and limitations of SAMP8 mice with the transgenic mouse as AD animal model. [ABSTRACT FROM AUTHOR]

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: The autocrine motility factor receptor (AMFR) is a multifunctional protein involved in cellular adhesion, proliferation, motility and apoptosis. Our study showed that increased AMFR protein expression in the hippocampus of KM mice correlated with enhanced capacity for learning and memory following the shuttle-box test and was significantly elevated in the highest score group. Also, AMF and AMFR mRNA expression positively correlates with the mRNA expression of the synapse marker synaptophysin (Syp). Aging studies in the senescence-accelerated mouse strain (SAM) prone/8 (SAMP8), an animal model of Alzheimer''s disease (AD), revealed significantly decreased mRNA and protein expression of AMF and AMFR in the hippocampus. This is especially true for AMFR and AMF protein expression compared with age-matched SAM resistant/1 (SAMR1) mouse strain as the control. Additionally, the low mRNA expression of AMFR could be up-regulated by the four nootropic traditional Chinese medicinal prescriptions (TCMPs): Ba-Wei-Di-Huang decoction (BW), Huang-Lian-Jie-Du decoction (HL), Dang-Gui-Shao-Yao-San (DSS) and Tiao-Xin-Fang decoction (TXF). AMFR protein expression could be up-regulated by two TCMPs, Liu-Wei-Di-Huang decoction (LW) and BW. This indicated that AMFR is involved in the process of learning and memory in the central nervous system. These results may provide useful clues for understanding the etiology of AD. [Copyright &y& Elsevier]

Abstract: (2)-Epigallocatechin-3-gallate (EGCG) is a major polyphenolic component of green tea. A number of studies have demonstrated EGCG has the possibility for delaying the onset or retarding the progression of Alzheimer’s disease (AD) and indicated EGCG possess inhibition of β-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen β-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of β-secretase activity with IC50 value of 7.57×10−7 M in screening assay, but then we found EGCG had significant fluorescence-quenching effect in confirming assay, this indicates EGCG has the false positive β-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the β-amyloid 1–40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit β-secretase cleavage activity. Overall this study illustrates that EGCG is not a β-secretase inhibitor based on the compelling data. This provides further support that the choice of complementary assay format or technology is a critical factor in molecular screening and drug development for improving the hit-finding capability and efficiency. [Copyright &y& Elsevier]

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: Liuwei Dihuang decoction (LW), a traditional Chinese medicinal prescription, enhances the cognitive function of CNS by significant modulating effects on some of the gene expressions. Expressions of genes, such as DUSP12, NSF, STUB1, CaMKIIα, AMFR, UQCRFS1 and other 11 novel genes without any functional clues changed significantly. These genes are involved in the protein-tyrosine phosphatase family, the AAA (ATPases associated with diverse cellular activities) gene family, the serine/threonine protein kinases family, ubiquitin ligase, mitochondrial function and so on. [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]

Abstract: JD-30 is an active fraction extracted from Danggui–Shaoyao–San (DSS), a traditional Chinese medicinal prescription. We previously showed that JD-30 could alleviate cognitive dysfunction of the mice induced by intracerebroventricular injection of β-amyloid (Aβ). However, data remain scarce on the effect of JD-30 on an Alzheimer''s disease (AD) model and the underlying mechanisms are unknown. Further detailed studies on the effects of JD-30 on spatial cognition of senescence-accelerated mouse prone 8 (SAMP8), a suitable rodent model for cognitive impairment of aged subjects were investigated to elucidate the possible mechanisms. Long-term treatment with JD-30 significantly decreased the prolonged latency of SAMP8 in the Morris water-maze test. It also ameliorated the reduction of long-term potentiation (LTP) and reduced the damage of neurons in the hippocampus of SAMP8. Finally, JD-30 decreased the content and deposition of Aβ in the brain of SAMP8. The results show that JD-30 improves deterioration of spatial learning and memory in the SAMP8 mouse model, and by decreasing the content and deposition of Aβ, neuronal activity and synaptic plasticity improve, suggesting one of the mechanisms involved. [Copyright &y& Elsevier]

Background: The toxicity of excessive glutamate release has been implicated in various acute and chronic neurodegenerative conditions. Vesicular glutamate transporters (VGLUTs) are the major mediators for the uptake of glutamate into synaptic vesicles. However, the dynamics and mechanism of this process in glutamatergic neurons are still largely unknown.Objective: This study aimed to investigate the candidate protein partners of VGLUT1 and their regulatory roles in the vesicles in rat brain.Methods: Pull down assay, co-immunoprecipitation assay, or split-ubiquitin membrane yeast two hybrid screening coupled with nanoRPLC-MS/MS were used to identify the candidate protein partners of VGLUT1 in the vesicles in rat brain. The in vitro and in vivo models were used to test effects of AβPP, Atp6ap2, Gja1, and Synataxin on VGLUT1 expression.Results: A total of 255 and 225 proteins and 172 known genes were identified in the pull down assay, co-immunoprecipitation assay, or split-ubiquitin yeast two-hybrid screening respectively. The physiological interactions of SV2A, Syntaxin 12, Gja1, AβPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AβPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AβPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models.Conclusion: These results elucidate that the AβPP and VGLUT1 interacts at vesicular level and AβPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a central nervous system (CNS) disease characterized by progressive cognitive dysfunction and memory loss. Qi Fu Yin is mainly used to treat dementia, particularly AD, in the clinic, but its comprehensive mechanisms are not known. In this research, we aimed to investigate the mechanisms of Qi Fu Yin in AD by network pharmacology and molecular docking. First, the chemical constituents in Qi Fu Yin were obtained from five databases and classified according to their structure. Targets of chemical constituents and AD-related targets were also collected from the databases. Then, overlapping genes between Qi Fu Yin and AD were identified by intersection analysis. MetaCore was used to gather enrichment information. Combination synergy analysis was performed by Cytoscape. After ligand-receptor docking, the binding affinity was verified by ADP-Glo™ kinase assay and fluorescence resonance energy transfer (FRET) assay. We found 12 classes with 977 components in Qi Fu Yin. A total of 511 compounds and 577 potential target proteins in Qi Fu Yin were found to be related to AD. The pathways of Qi Fu Yin in AD included oxidative stress and immune response. There was the best binding affinity between 11 pairs of genes and compounds. Furthermore, CDK5 was inhibited by nepetin with an IC 50 of 3.172 μM and kaempferol with an IC 50 of 2.659 μM. Ceanothic acid and 18 beta-glycyrrhetinic acid inhibited GSK3β, and the IC 50 values were 8.732 μM and 8.06 μM, respectively. Qi Fu Yin might alleviate Tau hyperphosphorylation by nepetin, kaempferol, ceanothic acid and 18 beta-glycyrrhetinic acid. • There were 12 classes with 977 components in Qi Fu Yin. • A total of 511 compounds and 577 potential target proteins in Qi Fu Yin were found to be related to AD. • The pathways of Qi Fu Yin in AD included oxidative stress and immune response. • CDK5 was inhibited by nepetin with an IC 50 of 3.172 μM and kaempferol with an IC 50 of 2.659 μM. • Ceanothic acid and 18 beta-glycyrrhetinic acid inhibited GSK3β, and the IC 50 values were 8.732 μM and 8.06 μM, respectively. [ABSTRACT FROM AUTHOR]

Four new acoranes [(I)-(III)], a novel cadinane (IV), and a novel guaiane (V) are isolated together with six known compounds. [ABSTRACT FROM AUTHOR]