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Senescence-accelerated mouse prone 8 (SAMP8) mice exhibit cognitive defects and neuron loss with aging, and were used to study anti-aging effects of Dendrobium nobile alkaloids (DNLA). DNLA (20 and 40 mg/kg) were orally administered to SAMP8 mice from 6 to 10 months of age. At 10-month of age, behavioral tests via Y-maze and Open-field and neuron damage via Nissl staining were evaluated. Protein was extracted and subjected to phosphorylated proteomic analysis followed by bioinformatic analysis. The cognitive deficits and neuron loss in hippocampus and cortex of aged SAMP8 mice were improved by DNLA. Hippocampal proteomic analysis revealed 196 differentially expressed protein/genes in SAMP8 compared to age-matched senescence-accelerated resistant SAMR1 mice. Gene Oncology enriched the tubulin binding, microtubule binding, and other activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed endocytosis, mRNA surveillance, tight junction, protein processing in endoplasmic reticulum, aldosterone synthesis and secretion, and glucagon signaling pathway changes. Upregulated protein/genes in the hippocampus of SAMP8 mice, such as Lmtk3, Usp10, Dzip1, Csnk2b, and Rtn1, were attenuated by DNLA; whereas downregulated protein/genes, such as Kctd16, Psd3, Bsn, Atxn2l, and Kif1a, were rescued by DNLA. The aberrant protein/gene expressions of SAMP8 mice were correlated with transcriptome changes of Alzheimer's disease in the Gene Expression Omnibus (GEO) database, and the scores were attenuated by DNLA. Thus, DNLA improved cognitive dysfunction and ameliorated neuronal injury in aged SAMP8 mice, and attenuated aberrant protein/gene expressions.
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Alcaloides , Enfermedad de Alzheimer , Dendrobium , Ratones , Animales , Proteómica , Alcaloides/farmacología , Envejecimiento , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , HipocampoRESUMEN
BACKGROUND/AIM: The ectopic pain associated with inferior alveolar nerve (IAN) injury has been reported to involve macrophage expression in the trigeminal ganglion (TG). However, the effect of age-related changes on this abnormal pain conditions are still unknown. This study sought to clarify the involvement of age-related changes in macrophage expression and phenotypic conversion in the TG and how these changes enhance ectopic mechanical allodynia after IAN transection (IANX). MATERIALS AND METHODS: We used senescence-accelerated mouse (SAM)-prone 8 (SAMP8) and SAM-resistance 1 (SAMR1) mice, which are commonly used to study ageing-related changes. Mechanical stimulation was applied to the whisker pad skin under light anaesthesia; the mechanical head withdrawal threshold (MHWT) was measured for 21 d post-IANX. We subsequently counted the numbers of Iba1 (macrophage marker)-immunoreactive (IR) cells, Iba1/CD11c (M1-like inflammatory macrophage marker)-co-IR cells, and Iba1/CD206 (M2-like anti-inflammatory macrophage marker)-co-IR cells in the TG innervating the whisker pad skin. After continuous intra-TG administration of liposomal clodronate Clophosome®-A (LCCA) to IANX-treated SAMP8-mice, the MHWT values of the whisker pad skin were examined. RESULTS: Five days post-IANX, the MHWT had significantly decreased in SAMP8 mice compared to SAMR1-mice. Iba1-IR and Iba1/CD11c-co-IR cell counts were significantly increased in SAMP8 mice compared to SAMR1 mice 5 d post-IANX. LCCA administration significantly restored MHWT compared to control-LCCA administration. CONCLUSION: Ectopic mechanical allodynia of whisker pad skin after IANX is exacerbated by ageing, which involves increases in M1-like inflammatory macrophages in the TG.
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Hiperalgesia , Traumatismos del Nervio Trigémino , Ratas , Ratones , Animales , Ratas Sprague-Dawley , Hiperalgesia/complicaciones , Hiperalgesia/metabolismo , Ganglio del Trigémino/metabolismo , Traumatismos del Nervio Trigémino/complicaciones , Traumatismos del Nervio Trigémino/metabolismo , Dolor Facial/complicaciones , Dolor Facial/metabolismo , Nervio Mandibular/metabolismo , Macrófagos/metabolismoRESUMEN
Growing evidence demonstrates the epigenetic modulation as a key event in Alzheimer's disease (AD) pathology. Furthermore, recent data suggests that the epigenetic regulation by the methyltransferase G9a is a crucial mechanism involved in learning and memory formation. Taking this into account, we hereby provide genomics data from pharmacological intervention with UNC0642, a potent and selective G9a/GLP in SAMP8 mice, a model of Alzheimer's disease (AD). We have generated novel RNA-seq and miRNA-seq data for three groups, healthy SAMR1, SAMP8 control and SAMP8 treated with UNC0642 (5 mg/Kg). Thus, the new data can be used to find miRNA regulation, and the mRNA's modified in AD under G9a/GLP inhibition.
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Activated microglia involved in the development of orofacial pain hypersensitivity have two major polarization states. The aim of this study was to assess the involvement of the aging-related phenotypic conversion of medullary microglia in the enhancement of intraoral pain sensitivity using senescence-accelerated mice (SAM)-prone/8 (SAMP8) and SAM-resistant/1 (SAMR1) mice. Mechanical head-withdrawal threshold (MHWT) was measured for 21 days post palatal mucosal incision. The number of CD11c-immunoreactive (IR) cells [affective microglia (M1)] and CD163-IR cells [protective microglia (M2)], and tumor-necrosis-factor-α (TNF-α)-IR M1 and interleukin (IL)-10-IR M2 were analyzed via immunohistochemistry on days 3 and 11 following incision. The decrease in MHWT observed following incision was enhanced in SAMP8 mice. M1 levels and the number of TNF-α-IR M1 were increased on day 3 in SAMP8 mice compared with those in SAMR1 mice. On day 11, M1 and M2 activation was observed in both groups, whereas IL-10-IR M2 levels were attenuated in SAMP8 mice, and the number of TNF-α-IR M1 cells increased, compared to those in SAMR1 mice. These results suggest that the mechanical allodynia observed following intraoral injury is potentiated and sustained in SAMP8 mice due to enhancement of TNF-α signaling, M1 activation, and an attenuation of M2 activation accompanying IL-10 release.
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Envejecimiento/inmunología , Dolor Facial/inmunología , Interleucina-10/metabolismo , Microglía/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos CD11/metabolismo , Modelos Animales de Enfermedad , Dolor Facial/etiología , Masculino , Ratones , Fenotipo , Receptores de Superficie Celular/metabolismo , Transducción de SeñalRESUMEN
Cognitive and behavioural disturbances are a growing public healthcare issue for the modern society, as stressful lifestyle is becoming more and more common. Besides, several pieces of evidence state that environment is crucial in the development of several diseases as well as compromising healthy aging. Therefore, it is important to study the effects of stress on cognition and its relationship with aging. To address these queries, Chronic Mild Stress (CMS) paradigm was used in the senescence-accelerated mouse prone 8 (SAMP8) and resistant 1 (SAMR1). On one hand, we determined the changes produced in the three main epigenetic marks after 4 weeks of CMS treatment, such as a reduction in histone posttranslational modifications and DNA methylation, and up-regulation or down-regulation of several miRNA involved in different cellular processes in mice. In addition, CMS treatment induced reactive oxygen species (ROS) damage accumulation and loss of antioxidant defence mechanisms, as well as inflammatory signalling activation through NF-κB pathway and astrogliosis markers, like Gfap. Remarkably, CMS altered mTORC1 signalling in both strains, decreasing autophagy only in SAMR1 mice. We found a decrease in glycogen synthase kinase 3 ß (GSK-3ß) inactivation, hyperphosphorylation of Tau and an increase in sAPPß protein levels in mice under CMS. Moreover, reduction in the non-amyloidogenic secretase ADAM10 protein levels was found in SAMR1 CMS group. Consequently, detrimental effects on behaviour and cognitive performance were detected in CMS treated mice, affecting mainly SAMR1 mice, promoting a turning to SAMP8 phenotype. In conclusion, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence.
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Envejecimiento/genética , Cognición , Epigénesis Genética , Estrés Psicológico/genética , Proteína ADAM10/genética , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Femenino , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND AND AIM: The aging-dependent activation of glycogen synthase kinase-3ß (GSK-3ß) has been suggested to be important in the onset of dementia. To discover novel therapeutic Kampo medicines for dementia, we examined the effects of orengedokuto (OGT; huáng lián jiedú tang) and san'oshashinto (SST; san huáng xiè xin tang) on memory deficits and GSK-3ß activity in senescence-accelerated prone mice (SAMP8). EXPERIMENTAL PROCEDURE: The object recognition test (ORT) and conditioned fear memory test (CFT) were employed to elucidate short-term working memory and long-term fear memory. The activity of GSK-3ß and the phosphorylation of related molecules were measured using a kinase assay and Western blotting. RESULTS AND CONCLUSION: OGT and SST attenuated memory deficits in SAMP8 in ORT, but not in CFT. In ex vivo experiments, cortical GSK-3ß activity was significantly stronger in SAMP8 than in SAMR1. The enhanced cortical GSK-3ß activity in SAMP8 was accompanied by a significant increase in the level of phosphorylated collapsin response mediator protein-2 (CRMP2), an important factor that is involved in the regulation of microtubule stability. OGT and SST attenuated not only increases in cortical GSK-3ß activity, but also the levels of phosphorylated CRMP2 in SAMP8. In vitro experiments, flavonoids contained in these kampo medicines, inhibited GSK-3ß activity in concentration-dependent manners. These results suggest that OGT and SST prevent aging-induced short-term working memory deficits by inhibiting aging-dependent elevations in the cortical GSK-3ß activity and subsequent CRMP2 phosphorylation.
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This data article contains the supporting information for the research article entitled "Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)" [1]. Senescence-accelerated mouse prone 8 (SAMP8), which originally developed from AKR/J mice, shows learning and memory impairments at the age of 8-12 months. However, little information is still available on phenotypical characteristics of younger SAMP8. To fully understand the phenotype of younger SAMP8, we optimized two behavioral tasks for SAMP8. In the object recognition task, 4-month-old SAMP8 made significantly more contacts with the familiar objects compared to age-matched SAMR1, however, distance traveled for both strains of mice were comparable. In the fear conditioning task, conventionally-used CS-US combination failed to induce robust conditioned fear in both strains of mice.
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Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12- and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA- and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1ß, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-ß, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.
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Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Longevidad/efectos de los fármacos , Subgrupos Linfocitarios/efectos de los fármacos , Envejecimiento/inmunología , Animales , Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Citocinas/inmunología , Citocinas/metabolismo , Inflamación/inmunología , Inflamación/prevención & control , Longevidad/inmunología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Melatonina/farmacología , Trastornos de la Memoria/inmunología , Trastornos de la Memoria/prevención & control , Ratones Endogámicos ICR , Ratones Endogámicos , Análisis de Componente PrincipalRESUMEN
Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people worldwide. Increasing evidence suggests that formaldehyde might be one of the various pathological mechanisms involved in the process of AD onset. Here, we use an AD mouse model, senescence accelerated mouse-prone 8 strain (SAMP8), to study the relationship between endogenous formaldehyde and impairment of cognition. The Morris water maze test was used to evaluate the spatial learning and memory ability of 3-month-old SAMP8 mice, and we correlated the results with endogenous formaldehyde concentrations in the brain. To investigate the underlying reasons for formaldehyde elevation in neurodegenerative diseases, the expression levels of enzymes involved in formaldehyde metabolism were analyzed, including (anabolic) semicarbazide sensitive amine oxidase (SSAO) and (catabolic) alcohol dehydrogenase III (ADH3). When compared with age-matched SAMR1 mice, we found that in 3-month-old SAMP8 mice the capacity for spatial learning and memory was lower, while brain formaldehyde levels were higher. By using real-time PCR, western blotting, enzyme assay, and immunohistochemistry techniques, we discovered that SSAO expression levels were increased, whereas ADH3 exhibited reduced expression levels of mRNA, protein, and enzyme activity. The imbalance of these metabolic enzymes may represent a causal explanation for the observed formaldehyde elevation in the SAMP8 brain. Such increase could be responsible for the observed tau hyperphosphorylation assumed to result in protein aggregation, ultimately leading to cognitive impairment. Taken together, our study gives new insights into the role of metabolic enzymes in age-related accumulation of formaldehyde, and thus the establishment of neurodegenerative diseases.
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Envejecimiento/metabolismo , Enfermedad de Alzheimer/complicaciones , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/metabolismo , Formaldehído/metabolismo , Envejecimiento/genética , Alcohol Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Amina Oxidasa (conteniendo Cobre) , Animales , Proteínas de Arabidopsis , Encéfalo/metabolismo , Moléculas de Adhesión Celular , Cromatografía Líquida de Alta Presión , Trastornos del Conocimiento/patología , Modelos Animales de Enfermedad , Transferasas Intramoleculares , Hígado/metabolismo , Masculino , Ratones , Factores de Tiempo , Proteínas tau/metabolismoRESUMEN
As a major characteristic of aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a newly identified risk gene for AD, which regulates inflammatory process in peripheral tissues via modulating the release of inflammatory cytokines. However, the role of TREM2 in aging-related neuroinflammation, cognitive deficiency, and AD-like neuropathology is unclear so far. Here, we detected the protein levels of TREM2 in brain of 3-, 7-, and 11-month-old senescence-accelerated mouse prone 8 (SAMP8) mice and observed that TREM2 levels were increased during aging process. We then knocked down TREM2 expression in brain of SAMP8 mice by nonviral RNA interference and found a significant increase in proinflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6, which was accompanied by a reduction in IL-10. Meanwhile, more obvious neuronal and synaptic losses and cognitive impairment were observed. These findings indicate that TREM2 may play a protective role against aging-related neuroinflammation and cognitive impairment.
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Envejecimiento/genética , Enfermedad de Alzheimer/genética , Trastornos del Conocimiento/genética , Técnicas de Silenciamiento del Gen , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/fisiología , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Envejecimiento/metabolismo , Enfermedad de Alzheimer/patología , Animales , Encéfalo/metabolismo , Trastornos del Conocimiento/patología , Citocinas/metabolismo , Progresión de la Enfermedad , Regulación hacia Abajo , Mediadores de Inflamación/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Mutantes Neurológicos , Neuronas/patología , ARN Interferente Pequeño , Receptores Inmunológicos/metabolismo , Sinapsis/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Deficits in cognition and performance accompanying age-related neurodegenerative diseases such as Alzheimer's disease (AD) are closely associated with the impairment of synaptic plasticity. Here, using a mouse model of senescence-accelerated P8 (SAMP8), we reported the role of tripchlorolide (T4), an extract of the natural herb Tripterygium wilfordii Hook F, in improving cognitive deficits and promoting the long-term potentiation (LTP) of hippocampal slices via the N-methyl-D-aspartate receptor (NMDAR)-dependent signaling pathway. Our results demonstrated that chronic administration of T4 at low doses (0.25, 1.0, or 4.0 µg/kg per day, injected intraperitoneally for 75 days) significantly improved learning and memory function in aged SAMP8 mice, as indicated by a chain of behavioral tests including the Y-maze and Morris water maze. Additionally, T4 reversed the impaired LTP in hippocampal CA1 regions of SAMP8 mice in a dose-dependent manner. Moreover, it upregulated the levels of phospho-NMDAR1, postsynaptic density-95 (PSD-95), phospho-calcium-calmodulin dependent kinase II (CaMKII), phospho-CREB and brain derived neurotrophic factor (BDNF) in the hippocampus. This indicates that T4 prevents the impairment of NMDAR-mediated synaptic plasticity-related signal molecules. At optimal doses, T4 did not show significant side-effects on blood counts, blood biochemical measures, or survival of the mice. This novel mechanism in reversing age-related synaptic dysfunction and NMDAR functional deficits suggests that T4 can halt the manifestation of a key early-stage event in AD. With the consideration of SAMP8 mice as a model to develop therapeutic interventions for AD, our findings provide new insight into the clinical application of tripchlorolide in AD treatment.
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Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Diterpenos/farmacología , Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fenantrenos/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/fisiopatología , Diterpenos/uso terapéutico , Hipocampo/fisiopatología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Plasticidad Neuronal/fisiología , Fenantrenos/uso terapéutico , Sinapsis/fisiologíaRESUMEN
The process of ageing has been repeatedly associated with increasing oxidative damage which has led to the hypothesis that reducing oxidative stress through antioxidant dietary factors may prolong lifespan. Ascorbic acid is an essential antioxidant in human diets and is widely used for supplementation. However, it is rather unclear if and to what extent ascorbic acid may affect lifespan in humans and model organisms. In our review of literature on vitamin C supplementation and its effect on lifespan in different model organisms we found that some studies suggest an increase in lifespan, other studies failed to observe any beneficial effect of vitamin C on longevity and some studies even reported a decrease in lifespan following vitamin C supplementation. Of the 14 studies included in our analysis, three were carried out in worms, four in flies and seven in rodents. The discrepancies between the studies may be related to species-specific differences, the concentration of vitamin C administered, the duration of supplementation and whether vitamin C was used alone or as part of a combined antioxidant diet. Potential underlying mechanisms through which vitamin C may influence lifespan and differences amongst species regarding the capacity to produce vitamin C endogenously are discussed.
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Ácido Ascórbico/administración & dosificación , Esperanza de Vida , Modelos Biológicos , Animales , HumanosRESUMEN
The microscopic and quantitative study reported here examined peroxidase-positive granules in the senescenceacceleration prone mouse (SAMP10) brain and the senescence-resistant mouse (SAMR1) brain. Three-month-old and 14-month-old SAMP10 and SAMR1 mice were used in this stusy. Coronal brain sections were made, and then incubated with medium containing 0.05% 3, 3'-diaminobenzidine and 0.003% H2O2 in 0.1 M PB to visualize endogenous peroxidase activity. Peroxidase-positive granules were rarely found in the three-month-old SAMR1, whereas a few positive granules were observed in the young SAMP10 brains. Forteen-month-old animals showed frequent labelling for endogenous peroxidase. This labelling was distributed exclusively in periventricular regions such as the periventricular and arcuate hypothalamic nuclei surrounding the third ventricle, and the periventricular portion of the caudate-putamen and lateral septal nuclei surrounding the lateral ventricle. Double labelling with GFAP antiserum indicated that most DAB-positive granules in these regions were located within astrocytes. Image analysis showed that significantly more peroxidase-positive granules occurred with advancing age in both the SAMP10 and SAMR1 brains. However, the amount of these inclusions was significantly greater in the young as well as the aged SAMP10 brain than in the age-matched SAMR1 controls. Electron microscopic examination of the aged SAMP10 brain showed localization of endogenous peroxidase in astrocytes. They appeared as accumulated granules or inclusion bodies with homogeneously high electron density, rather than as diffusely scattered small particles. In summary, DAB-stained granules indicating the presence of peroxidase activity accumulated with ageing in both SAMP10 and SAMR1 brains, mainly in astrocytes of the periventricular brain regions. Further, the accumulation was more accelerated from younger ages and more extensively in the SAMP10 brain. These results suggest that astroglial changes might occur from young period in the periventricular region of the SAMP10, which might be associated with the neurological senescence in the SAMP10.