Effects of Qi-Fu-Yin on aging of APP/PS1 transgenic mice by regulating the intestinal microbiome.

Introduction: Alzheimer's disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown. Methods: We used 11-month-old APP/PS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results. Results: Here we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP/ PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APP/PS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APP/PS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2_Glycos_transf_2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6. Conclusion: Our results indicated that the effects of Qi-Fu-Yin anti-aging of APP/PS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.

Proteome Profiling Identified Amyloid-ß Protein Precursor as a Novel Binding Partner and Modulator of VGLUT1.

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 AßPP, 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, AßPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AßPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AßPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models. CONCLUSION: These results elucidate that the AßPP and VGLUT1 interacts at vesicular level and AßPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities.

A network pharmacology-based study on key pharmacological pathways and targets of Qi Fu Yin acting on Alzheimer's disease.

BACKGROUND: 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. OBJECTIVE: In this research, we aimed to investigate the mechanisms of Qi Fu Yin in AD by network pharmacology and molecular docking. METHODS: 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. RESULTS: 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 IC50 of 3.172 µM and kaempferol with an IC50 of 2.659 µM. Ceanothic acid and 18 beta-glycyrrhetinic acid inhibited GSK3ß, and the IC50 values were 8.732 µM and 8.06 µM, respectively. CONCLUSION: Qi Fu Yin might alleviate Tau hyperphosphorylation by nepetin, kaempferol, ceanothic acid and 18 beta-glycyrrhetinic acid.

Characteristics of the traditional Liu-Wei-Di-Huang prescription reassessed in modern pharmacology.

Liu-Wei-Di-Huang (LW) is a Yin nourishing and kidney tonifying prescription in traditional Chinese medicine with promising pharmacological characteristics that can be further exploited and developed in modern medicine. We provide a comprehensive and detailed literature report on the clinical and experimental pharmacology of LW, including its quality control parameters, phytochemistry, pharmacokinetics, and toxicology. Our literature review indicates that the LW prescription possesses a unique combination of pharmacological characteristics that can be safely used for treating very different diseases. Quality control and pharmacokinetic parameters of LW are mostly based on its major bioactive phytochemical constituents. We postulate that modulating or rebalancing the neuroendocrine immunomodulation network in the body is the underlying mechanism of the multiple pharmacological activities displayed by LW.

SOD mimicAEOL-10150 improve lifespan and delay brain aging via inhibition of senescence-associated secretory phenotype in SAMR1 strain / 中国药理学与毒理学杂志

OBJECTIVE To observe the anti-aging effects of SOD mimicAEOL-10150 in anti-senescence accelerated mouse resistant 1 (SAMR1) strain. METHODS The lifespan of SAMR1 mice were observed by subcutaneous injection AEOL-101502 mg·kg- 1 once a week. Morris water maze, new object recognition, nesting and forced swimming were used to observe the behavioral changes of animals. Lymphocyte subgroups and ROS were measured by Flow cytometry. The cytokines levels were determined by Luminex method. The number of DCX + neurons in brain tissue was observed by immunofluorescence. RESULTS The results showed that AEOL-10150 could prolong the mean lifespan of SAMR1 mice, but it had no obvious effect on maximal lifespan. What's more, AEOL-10150 could significantly improve the spatial learning memory of aged mice, but it could not increase the number of DCX+ neurons in the hypothalamic MBH and hippocampal DG regions. Then, we observed the effects of AEOL-10150 on peripheral blood lymphocyte subgroups and cytokines. We found that AEOL-10150 significantly modulated the lymphocyte subgroups and cytokine release. Especially, AEOL-10150 can dose-dependently inhibit plasma levels of SASP related inflammatory cytokines TNF-α and IL-17. CONCLUSION The results indicate that AEOL-10150 has anti-aging effects, and the effects are closely related to modulating immunity and inhibiting SASP production.

Effects of LW-AFC, a new formula derived from Liuwei Dihuang decoction, on intestinal microbiome in senescence-accelerated mouse prone 8 strain, a mouse model of Alzheimer disease / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effects of LW-AFC, a new formula derived from Liuwei Dihuang decoction, on gut microbiota and the behavior of learning and memory of SAMP8 mice, a mouse model of Alzheimer Disease (AD), and identify the specific intestinal microbiota correlating with cognitive ability. METHODS Morris-water maze test, novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory. 16S rRNA amplicon sequencing (Illumina, San Diego, CA, USA) was employed to investigate gut microbiota. RESULTS The treatment of LW- AFC improved cognitive impairments of SAMP8 mice, including spatial learning and memory ability, active avoidance response, and object recognition memory capability. Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units (OTUs) in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. The treatment of LW- AFC altered 22 (16 increased and 6 decreased) OTUs in SAMP8 mice and among them, 15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice. We further showed that there were 7 (3 negative and 4 positive correlation) OTUs significantly correlated with all the three types of cognitive abilities, at the order level, including Bacteroidales, Clostridiales, Desulfovibrionales, CW040, and two unclassified orders. LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice. CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.

LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune abnormalities in PrP-hAβPPswe/PS1ΔE9 transgenic mice / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of LW- AFC, a new formula of the main active components extracted from Liuwei Dihuang decoction, on treatment of Alzheimer disease (AD) in mouse models. METHODS After treatment LW- AFC, mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-β(Αβ) deposition, and Αβ level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an ELISA were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. RESULTS LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Αβ deposition in the brain, and reduced the concentration of Aβ1- 42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle- stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+T cells, and reduced CD4+CD25+Foxp3+T cells in the spleen lymphocytes, down- regulated interleukin(IL)- 1β, IL- 2, IL- 6, IL- 23, granulocyte- macrophage colony stimulating factor, and tumor necrosis factor-α and -β, and up-regulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice. CONCLUSION LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic micevia the restoration of the NIM network to a greater extent than either memantineor donepezil, which supports the use of LW-AFC as a potential agent for AD therapy.

LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAßPPswe/PS1ΔE9 transgenic mice.

BACKGROUND: Accumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer's disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP-hAßPPswe/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. METHODS: After treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-ß (Aß) deposition, and Aß level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student's t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett's post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test. RESULTS: LW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Aß deposition in the brain, and reduced the concentration of Aß1-42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+ T cells, and reduced CD4+CD25+Foxp3+ T cells in the spleen lymphocytes, downregulated interleukin (IL)-1ß, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-α and -ß, and upregulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice. CONCLUSIONS: LW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy.

Neuroendocrine immunomodulation network dysfunction in SAMP8 mice and PrP-hAßPPswe/PS1ΔE9 mice: potential mechanism underlying cognitive impairment.

Senescence-accelerated mouse prone 8 strain (SAMP8) and PrP-hAßPPswe/PS1ΔE9 (APP/PS1) mice are classic animal models of sporadic Alzheimer's disease and familial AD respectively. Our study showed that object recognition memory, spatial learning and memory, active and passive avoidance were deteriorated and neuroendocrine immunomodulation (NIM) network was imbalance in SAMP8 and APP/PS1 mice. SAMP8 and APP/PS1 mice had their own specific phenotype of cognition, neuroendocrine, immune and NIM molecular network. The endocrine hormone corticosterone, luteinizing hormone and follicle-stimulating hormone, chemotactic factor monocyte chemotactic protein-1, macrophage inflammatory protein-1ß, regulated upon activation normal T cell expressed and secreted factor and eotaxin, pro-inflammatory factor interleukin-23, and the Th1 cell acting as cell immunity accounted for cognitive deficiencies in SAMP8 mice, while adrenocorticotropic hormone and gonadotropin-releasing hormone, colony stimulating factor granulocyte colony stimulating factor, and Th2 cell acting as humoral immunity in APP/PS1 mice. On the pathway level, chemokine signaling and T cell receptor signaling pathway played the key role in cognition impairments of two models, while cytokine-cytokine receptor interaction and natural killer cell mediated cytotoxicity were more important in cognitive deterioration of SAMP8 mice than APP/PS1 mice. This mechanisms of NIM network underlying cognitive impairment is significant for further understanding the pathogenesis of AD and can provide useful information for development of AD therapeutic drug.

A Co-Module Regulated by Therapeutic Drugs in a Molecular Subnetwork of Alzheimer's Disease Identified on the Basis of Traditional Chinese Medicine and SAMP8 Mice.

There are currently no approved effective therapies for Alzheimer's disease (AD). AD is a classic, multifactorial, complex syndrome. Thus, a polypharmacological or multitargeted approach to AD might provide better therapeutic benefits than monotherapies. However, it remains elusive which biological processes and biomolecules involved in the pathophysiologic processes of AD would constitute good targets for multitargeted therapy. This study proposes that a co-module, consisting of biological processes, cellular pathways and nodes, in a molecular subnetwork perturbed by different therapeutic drugs may be the optimal therapeutic target for an AD multitarget-based intervention. Based on this hypothesis, genes regulated in the hippocampus and cortex of senescence-accelerated mouse prone-8 (SAMP8) mice by traditional Chinese medicine (TCM) prescriptions with different constituents and the same beneficial effects on AD, including the decoctions Liu-Wei-Di-Huang (LW), Ba-Wei-Di-Huang (BW), Danggui-Shaoyao-San (DSS), Huang-Lian-Jie-Du (HL) and Tiao-Xin-Fang (TXF), were investigated via cDNA microarray, and the perturbed subnetworks were constructed and interpreted. After comparing 15 perturbed subnetworks based on genes affected by LW, BW, HL, DSS and TXF, the results showed that the most important common nodes perturbed by these interventions in the brains of SAMP8 mice were RPS6KA1 and FHIT, and that other important common nodes included UBE2D2, STUB1 and AMFR. These five drugs simultaneously and significantly disturbed the regulation of apoptosis and protein ubiquitination among biological processes. These nodes and processes were key components of the co-module regulated by therapeutic drugs in a molecular subnetwork of AD. These results suggest that targeting candidate regulator of apoptosis and protein ubiquitination might be effective for AD treatment, and that RPS6KA1, FHIT, UBE2D2, STUB1 and AMFR might be optimal combinational targets of an AD multitarget-based therapy.

The behavioral, pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer's disease animal model.

Alzheimer's disease (AD) is a widespread and devastating progressive neurodegenerative disease. Disease-modifying treatments remain beyond reach, and the etiology of the disease is uncertain. Animal model are essential for identifying disease mechanisms and developing effective therapeutic strategies. Research on AD is currently being carried out in rodent models. The most common transgenic mouse model mimics familial AD, which accounts for a small percentage of cases. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging. Many studies indicate that SAMP8 mice harbor the behavioral and histopathological signatures of AD, namely AD-like cognitive and behavioral alterations, neuropathological phenotypes (neuron and dendrite spine loss, spongiosis, gliosis and cholinergic deficits in the forebrain), ß-amyloid deposits resembling senile plaques, and aberrant hyperphosphorylation of Tau-like neurofibrillary tangles. SAMP8 mice are useful in the development of novel therapies, and many pharmacological agents and approaches are effective in SAMP8 mice. SAMP8 mice are considered a robust model for exploring the etiopathogenesis of sporadic AD and a plausible experimental model for developing preventative and therapeutic treatments for late-onset/age-related AD, which accounts for the vast majority of cases.

Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model.

Harboring the behavioral and histopathological signatures of Alzheimer's disease (AD), senescence accelerated mouse-prone 8 (SAMP8) mice are currently considered a robust model for studying AD. However, the underlying mechanisms, prioritized pathways and genes in SAMP8 mice linked to AD remain unclear. In this study, we provide a biological interpretation of the molecular underpinnings of SAMP8 mice. Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age-matched SAMR1 mice at 2, 6, and 12 months of age using cDNA microarray analysis. On the basis of PPI, MetaCore and the co-expression network, we constructed a distinct genetic sub-network in the brains of SAMP8 mice. Next, we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice. We found abnormal gene expression of RAF1, MAPT, PTGS2, CDKN2A, CAMK2A, NTRK2, AGER, ADRBK1, MCM3AP, and STUB1, which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice. Specifically, we found microRNAs, including miR-20a, miR-17, miR-34a, miR-155, miR-18a, miR-22, miR-26a, miR-101, miR-106b, and miR-125b, that might regulate the expression of nodes in the sub-network. Taken together, these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro-pathogenesis in SAMP8 mice from a systems perspective.

Autocrine motility factor receptor is involved in the process of learning and memory in the central nervous system.

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.

The green tea polyphenol (2)-epigallocatechin-3-gallate (EGCG) is not a ß-secretase inhibitor.

(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 ß-secretase activity. We utilized homogeneous time-resolved fluorescence assay with a substrate Eu-CEVNLDAEFK-Qsy7 to screen ß-secretase inhibitor in a cell-free system and AlphaLISA assay in cell system. The results first showed that EGCG had significant inhibition of ß-secretase activity with IC(50) 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 ß-secretase inhibitory activity. Furthermore, the followed AlphaLISA assay based on cell showed EGCG did not reduce the ß-amyloid 1-40 secretion in HuAPPswe/HuBACE1 Chinese hamster ovary cell without affecting cell viability. Therefore our findings indicate EGCG do not inhibit ß-secretase cleavage activity. Overall this study illustrates that EGCG is not a ß-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.

The activity and mRNA expression of ß-secretase, cathepsin D, and cathepsin B in the brain of senescence-accelerated mouse.

The senescence accelerated mouse prone 8 (SAMP8), an animal model of Alzheimer's disease, has amyloid-ß deposition in the brain. This study showed that ß-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. ß-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 ß-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 ß-secretase activity and the increased amyloid-ß 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 ß-secretase inhibitor.

[Treatment of post stroke cognitive impairment by rTMS].

Repetitive transcranial of magnetic stimulation (rTMS), as a new electrophysiological technique, has been used in treating neurological and psychiatric diseases in clinical. In recent years, rTMS has also been employed to explore the treatment options for post stroke cognitive impairment (PSCI). Studies showed that rTMS was beneficial to recovery of post-stroke aphasia, improvement of memory dysfunction and alleviation of hemispatial neglect. Moreover, it is safe for patient within the recommended parameters of safety guidance. rTMS exerts therapeutic effects by interfering with the reconstruction of cortical network, improving the cerebral blood flow and metabolism, adjusting the ion balance by modulating cortical excitability. In addition, rTMS could enhance synaptic plasticity, inhibit the apoptosis, and regulate the transmission of a variety of neurotransmitters. It was reviewed that the basic principles of rTMS, the efficacy, safety and mechanism of rTMS in the treatment of PSCI, as well as the current problems and prospects in this paper.

JD-30, an active fraction extracted from Danggui-Shaoyao-San, decreases ß-amyloid content and deposition, improves LTP reduction and prevents spatial cognition impairment in SAMP8 mice.

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 ß-amyloid (Aß). 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 Aß 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 Aß, neuronal activity and synaptic plasticity improve, suggesting one of the mechanisms involved.

Expression of VGLUTs contributes to degeneration and acquisition of learning and memory.

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.

[Ideas of systems biology on study of traditional Chinese medicine].

Traditional Chinese medicine (TCM) is the scientific therapeutics derived from the traditional Chinese physician's considerable clinical practice during the long history, with the characteristic of significant clinical therapeutic effects. The therapeutic philosophy of TCM is integrative medicine and pattern differentiation. The ideas of systems biology on the study of TCM were formed after the micro-and macro-outcome of systems biology being used into the practice of study on TCM. It is very important for the inheritance and development of TCM to disclose the basic mechanism of the clinical therapeutic effects of TCM and find new drugs, from the herbal preparation, pharmacology and pharmacokinetic to drug development using modern science technologies based on the theory of TCM.

[Survey of studies on the mechanism of acupuncture and moxibustion treating diseases abroad].

Acupuncture is a medical technique with national and cultural characteristics in traditional Chinese medicine with a less adverse reaction and obvious therapeutic effect. Modern medical theoretical basis about acupuncture treating many diseases is preliminarily discovered accompanying with the combination of traditional Chinese medicine and western medicine. This paper reviewed advances of the studies on the mechanisms of acupuncture treatment, and acupuncture treating pain, nausea and vomiting, neurodegenerative diseases, cerebrovascular and cardiovascular diseases and so on in recent years abroad.