Senescence-accelerated Mouse Prone 8 Research Articles

Inhibition of the CXCL12/CXCR4 axis prevents periurethral collagen accumulation and lower urinary tract dysfunction in vivo.

Several studies show that prostatic fibrosis is associated with male lower urinary tract dysfunction (LUTD). Development of fibrosis is typically attributed to signaling through the transforming growth factor β (TGF-β) pathway, but our laboratory has demonstrated that in vitro treatment of human prostatic fibroblasts with the C-X-C motif chemokine ligand 12 (CXCL12) chemokine stimulates myofibroblast phenoconversion and that CXCL12 has the capacity to activate profibrotic pathways in these cells in a TGF-β-independent manner. We have previously reported that feeding mice high-fat diet (HFD) results in obesity, type II diabetes, increased prostatic fibrosis, and urinary voiding dysfunction. The purpose of this study was to test the hypothesis that in vivo blockade of the CXCL12/CXCR4 axis would inhibit the development of fibrosis-mediated LUTD in HFD-fed mice. Two-month-old male senescence-accelerated mouse prone-6 mice were fed either a HFD or low-fat diet (LFD) for 8 months. Half of each dietary group were given constant access to normal water or water that contained the C-X-C chemokine receptor type 4 (CXCR4; CXCL12 receptor) antagonist CXCR4AIII. At the conclusion of the study, mice were weighed, subjected to oral glucose tolerance testing and cystometry, and lower urinary tract tissues collected and assessed for collagen content. HFD-fed mice became significantly obese, insulin resistant, and hyperglycemic, consistent with acquisition of metabolic syndrome, compared with LFD-fed mice. Anesthetized cystometry demonstrated that HFD-fed mice experienced significantly longer intercontractile intervals and greater functional bladder capacity than LFD-fed mice. Immunohistochemistry demonstrated high levels of CXCR4 and CXCR7 staining in mouse prostate epithelial and stromal cells. Picrosirius red staining indicated significantly greater periurethral collagen deposition in the prostates of HFD than LFD-fed mice. Treatment with the CXCR4 antagonist CXCR4AIII did not affect acquisition of metabolic syndrome but did reduce both urinary voiding dysfunction and periurethral prostate collagen accumulation. This is the first study to report that obesity-induced lower urinary tract fibrosis and voiding dysfunction can be repressed by antagonizing the activity of the CXCR4 chemokine receptor in vivo. These data suggest that targeting the CXCL12/CXCR4 signaling pathway may be a clinical option for the prevention or treatment of human male LUTD.

Effects of manual acupuncture combined with donepezil in a mouse model of Alzheimer's disease.

To explore whether combined therapy with donepezil and acupuncture is better than treatment with donepezil or acupuncture individually in a rat model of Alzheimer's disease. In this study, we randomly divided 40 7.5-month-old senescence-accelerated mouse prone 8 (SAMP8) male mice into four groups: SAMP8, SAMP8+D, SAMP8+MA and SAMP8+D+MA. An additional 10 7.5-month-old SAMR1 male mice were included as a healthy control group (SAMR1). Mice in the SAMP8+D group were given donepezil at a dose of 0.65 µg/g/day; mice in the SAMP8+MA group underwent manual acupuncture at GV20, GV26 and Yintang for 20 min per day; mice in the SAMP8+D+MA received both donepezil and manual acupuncture; and mice in the SAMR1 and SAMP8 groups underwent restraint only to control for the effects of handling. After the 15-day treatment, the Morris water maze test, micro-PET(positron-emission tomography), H&E (haematoxylin and eosin) staining, and immunohistochemistry were used to study the differences between donepezil (SAMP8+D), acupuncture (SAMP8+MA), and donepezil combined with acupuncture (SAMP8+D+MA) therapy for the treatment of Alzheimer's disease. We found that, compared with the untreated SAMP8 group, donepezil, manual acupuncture, and combined therapy with donepezil and manual acupuncture all improved spatial learning and memory ability, the level of glucose metabolism in the brain, and the content of Aβ amyloid in the cortex. Moreover, combined therapy outperformed treatment with donepezil or acupuncture individually in the SAMP8 mice. This study shows that the combination of manual acupuncture and donepezil in an Alzheimer's disease animal model is superior to acupuncture and donezepil alone. However, randomised controlled trials should be undertaken to clarify the clinical efficacy of combination therapy.

Long-term dietary supplementation with the green tea cultivar Sunrouge prevents age-related cognitive decline in the senescence-accelerated mouse Prone8.

A majority of the potential health benefits of green tea, including the potential to prevent cognitive decline, have been attributed to epigallocatechin gallate (EGCG). Sunrouge is a green tea cultivar that contains EGCG and several other bioactive components such as quercetin, myricetin, cyanidin and delphinidin. We compared the effects of Sunrouge and Yabukita, the most popular Japanese green tea cultivar, on cognitive function in the senescence-accelerated mouse Prone8. These mice were fed an experimental diet containing Sunrouge extract (SRE) or Yabukita extract (YBE). SRE feeding significantly prevented cognitive decline, whereas YBE feeding had little effect. Moreover, SRE feeding prevented elevation of the amyloid-β42 level while improving the gene expression of neprilysin and decreasing beta-site APP-cleaving enzyme 1 in the brain. These preventive effects of SRE against cognitive decline were attributed to the characteristic composition of Sunrouge and strongly suggest that consumption of this cultivar could protect against age-related cognitive decline.

Fermentation Improves the Preventive Effect of Soybean Against Bone Loss in Senescence-Accelerated Mouse Prone 6.

Osteopenia is a preclinical phase of osteoporosis, it occurs naturally with aging and increases the risk of bone fractures in elderly males. Previous studies have revealed the beneficial effects of soybean on preventing bone loss due to its isoflavone contents. Fermentation alters the soybean isoflavone contents, that is, isoflavone glucosides is hydrolyzed into aglycones. However, it is not clear how these alterations influences the preventive effect of soybean on bone loss. In this study, we fed senescence-accelerated mouse prone 6 (SAMP6), a model of senile osteopenia, with an equal dosage of nonfermented soybean (NS) or fermented soybean, Doenjang (DJ) for 18 weeks. Mice supplemented with DJ showed 1.13-fold higher bone densities and 1.06-fold longer relative bone lengths than those of osteopenic SAMP6 mice old control (OC), while NS-supplemented mice showed no significant improvement. Supplementation with DJ effectively prevented bone loss in the osteopenia model by the improvement of bone formation and reduction of osteoclastogenesis. In addition, we discovered that DJ increased osteogenesis in SAMP6 mice via BMP2-Smad-Runx2 signaling. These results suggest that the fermentation process could enhance bone loss prevention by soybean and dietary supplementation with fermented soybeans may be beneficial for bone health. PRACTICAL APPLICATION: Soybean fermentation improved the preventive effects of soybean on bone loss. Therefore, the consumption of fermented soybean, Doenjang, is a potential alternative for aging-related bone loss therapy.

Lactobacillus paracasei PS23 decelerated age-related muscle loss by ensuring mitochondrial function in SAMP8 mice.

Sarcopenia is a common impairment in the elderly population responsible for poor outcomes later in life; it can be caused by age-related alternations. Only a few strategies have been reported to reduce sarcopenia. Lactobacillus paracasei PS23 (LPPS23) has been reported to delay some age-related disorders. Therefore, here we investigated whether LPPS23 decelerates age-related muscle loss and its underlying mechanism. Female senescence-accelerated mouse prone-8 (SAMP8) mice were divided into three groups (n=6 each): non-aging (16-week-old), control (28-week-old), and PS23 (28-week-old) groups. The control and PS23 groups were given saline and LPPS23, respectively. We evaluated the effects of LPPS23 by analyzing body weight and composition, muscle strength, protein uptake, mitochondrial function, reactive oxygen species (ROS), antioxidant enzymes, and inflammation-related cytokines. LPPS23 significantly attenuated age-related decreases of muscle mass and strength. Compared to the control group, the non-aging and PS23 groups exhibited higher mitochondrial function, IL10, antioxidant enzymes, and protein uptake. Moreover, inflammatory cytokines and ROS were lower in the non-aging and PS23 groups than the control group. Taken together, LPPS23 extenuated sarcopenia progression during aging; this effect might have been enacted by preserving the mitochondrial function via reducing age-related inflammation and ROS and by retaining protein uptake in the SAMP8 mice.

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated β-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

3,4,5-Tricaffeoylquinic acid induces adult neurogenesis and improves deficit of learning and memory in aging model senescence-accelerated prone 8 mice.

Caffeoylquinic acid (CQA) is a natural polyphenol with evidence of antioxidant and neuroprotective effects and prevention of deficits in spatial learning and memory. We studied the cognitive-enhancing effect of 3,4,5-tricaffeoylquinic acid (TCQA) and explored its cellular and molecular mechanism in the senescence-accelerated mouse prone 8 (SAMP8) model of aging and Alzheimer’s disease as well as in human neural stem cells (hNSCs). Mice were fed with 5 mg/kg of TCQA for 30 days and were tested in the Morris water maze (MWM). Brain tissues were collected for immunohistochemical detection of bromodeoxyuridine (BrdU) to detect activated stem cells and newborn neurons. TCQA-treated SAMP8 exhibited significantly improved cognitive performance in MWM compared to water-treated SAMP8. TCQA-treated SAMP8 mice also had significantly higher numbers of BrdU+/glial fibrillary acidic protein (GFAP+) and BrdU+/Neuronal nuclei (NeuN+) cells in the dentate gyrus (DG) neurogenic niche compared with untreated SAMP8. In hNSCs, TCQA induced cell cycle arrest at G0/G1, actin cytoskeleton organization, chromatin remodeling, neuronal differentiation, and bone morphogenetic protein signaling. The neurogenesis promoting effect of TCQA in the DG of SAMP8 mice might explain the cognition-enhancing influence of TCQA observed in our study, and our hNSCs in aggregate suggest a therapeutic potential for TCQA in aging-associated diseases.

Dietary Fructooligosaccharide and Glucomannan Alter Gut Microbiota and Improve Bone Metabolism in Senescence-Accelerated Mouse.

Gut microbiota improved using prebiotics may delay the onset of senescence-related health problems. We hypothesized that prolonged intake of prebiotics delays senile osteoporosis. Forty-five male senescence-accelerated mouse prone 6 (SAMP6) aged four weeks were raised on 5% fructooligosaccharide (FOS), 5% glucomannan (GM), or a control diet for 31 weeks. Gut microbiota were identified using culture-dependent analytical methods. Mineral content in femoral bone was analyzed using atomic absorption spectrophotometry. Bone metabolism and inflammatory markers were measured using enzyme-linked immunosorbent assay. The numbers of Lactobacillus and Bacteroides in cecal contents were significantly higher in the FOS than in the control group ( p < 0.05); the number of Clostridium was significantly higher in the GM than in the control group ( p < 0.05). Calcium content was significantly higher in the femoral bones of the FOS group (30.5 ± 0.8 mg) than in the control group (27.5 ± 1.5 mg) ( p < 0.05). There was no difference between the GM (29.1 ± 2.0 mg) and control groups. During senescence, urinary deoxypyridinoline and serum high-sensitivity C-reactive protein levels significantly decreased in the FOS (1.2 ± 0.2 nmol/3 d and 80 ± 6.1 ng/100 mL) and GM groups (1.2 ± 0.2 nmol/3 d and 80 ± 6.1 ng/100 mL) compared with the control group (1.8 ± 0.5 nmol/3 d and 93 ± 7.4 ng/100 mL) ( p < 0.05). Thus, dietary FOS and GM modified gut microbiota and reduced bone resorption by reducing systemic inflammation in SAMP6.

Effect of olive oil consumption on aging in a senescence-accelerated mice-prone 8 (SAMP8) model.

Background : Mediterranean diets have been linked to a reduced risk of cancer, vascular illnesses, Parkinson's and Alzheimer's disease. Olive oil is the primary fat source in the Mediterranean diet ; however, only a few studies have investigated the effect of olive oil on aging. In the present study, we aimed to determine whether consumption of olive oil significantly influences aging and memory in senescence-accelerated mouse-prone 8 (SAMP8). Methods : SAMP8 and senescence-accelerated mouse resistant 1 (SAMR1) mice were fed either 7% soy oil or 1% olive oil and 6% soy oil during a six-month study period. Reduction in memory in passive avoidance learning was examined after two months from the initiation of the experiment. Results : The weight of organs including the liver, kidney, spleen, and fat tissue changed significantly and memory performance was reduced in SAMP8 than in SAMR1 mice. There were no significant differences in SAMP8 and SAMR1 mice; however, blood triglyceride level decreased significantly in SAMP8 mice fed on olive oil. Conclusions : These results suggest that consuming olive oil may not have a protective role in aging and memory recall, but beneficial effects may be related to improvement in lipid metabolism. J. Med. Invest. 66 : 241-247, August, 2019.

Early attenuation of autonomic nervous function in senescence accelerated mouse-prone 8 (SAMP8).

The senescence-accelerated mouse (SAM) strain has been established as an inbred strain with an accelerated aging phenotype. SAM prone-8 (SAMP8), one of the SAM strain, exhibits learning disability, immune deficiency, and circadian rhythm loss at a relatively young age. However, it has not been clarified whether aging affects the autonomic nervous activity in SAMP8. The aim of this study was to clarify the utility of SAMP8 in age-related studies of autonomic nervous function. Electrocardiogram (ECG), body temperature, and locomotor activity were recorded to evaluate bio-behavioral activities. Autonomic nervous activity was evaluated via power spectral analysis of heart rate variability from ECG recordings. SAMP8 significantly decreased both biological and autonomic nervous functions, and the animals exhibited circadian rhythm loss of locomotive activity at as early as 40 weeks of age compared with a control strain at the same age. We concluded that the SAMP8 strain can be used as an animal model for age-related studies of autonomic nervous function.

Age-related changes of senescence-accelerated mouse prone 10 (SAMP10) mice as an animal model for AD

Age-related changes of senescence-accelerated mouse prone 10 (SAMP10) mice as an animal model for AD

Orengedokuto and san'oshashinto improve memory deficits by inhibiting aging-dependent activation of glycogen synthase kinase-3β

Background and aimThe aging-dependent activation of glycogen synthase kinase-3β (GSK-3β) 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; 黃連解毒湯 huáng lián jiědú tāng) and san'oshashinto (SST; 三黃瀉心湯 sān huáng xiè xīn tāng) on memory deficits and GSK-3β activity in senescence-accelerated prone mice (SAMP8). Experimental procedureThe 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-3β and the phosphorylation of related molecules were measured using a kinase assay and Western blotting. Results and conclusionOGT and SST attenuated memory deficits in SAMP8 in ORT, but not in CFT. In ex vivo experiments, cortical GSK-3β activity was significantly stronger in SAMP8 than in SAMR1. The enhanced cortical GSK-3β 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-3β activity, but also the levels of phosphorylated CRMP2 in SAMP8. In vitro experiments, flavonoids contained in these kampo medicines, inhibited GSK-3β 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-3β activity and subsequent CRMP2 phosphorylation.

Association of gut microbiota composition and function with a senescence-accelerated mouse model of Alzheimer's Disease using 16S rRNA gene and metagenomic sequencing analysis.

Although an intriguing potential association of the gut microbiome with Alzheimer's disease (AD) has attracted recent interest, few studies have directly assessed this relationship or underlying mechanism. Here, we compared the gut microbiota composition and functional differentiation of senescence-accelerated mouse prone 8 (SAMP8) mice with control senescence-accelerated mouse resistant 1 (SAMR1) mice using 16S rRNA gene and metagenomic sequencing analysis, respectively. Specifically, 16S sequencing results showed that the SAMP8 mice displayed a characteristic composition of the gut microbiome that clearly differed from that of the SAMR1 mice. Moreover, network analysis revealed that the gut microbiota of SAMP8 mice had decreased correlation density and clustering of operational taxonomic units. Metagenomic results revealed that the predominant Cluster of Orthologous Groups functional category related to these changes was the metabolism cluster in SAMP8 mice. The Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further demonstrated enrichment of the relative abundance of some dominant metabolism-related KEGG pathways in the SAMP8 mice, consistent with the suggested pathogenic mechanisms of AD. In conclusion, this study suggests that perturbations of the gut microbiota composition and the functional metagenome may be associated with AD. Further studies are warranted to elucidate the potential new mechanism contributing to AD progression.

Temporal Integrative Analysis of mRNA and microRNAs Expression Profiles and Epigenetic Alterations in Female SAMP8, a Model of Age-Related Cognitive Decline.

A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered a useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages compared to age-matched SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively; 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression toward a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer's Disease (AD) and age-related cognitive impairment.

Pseudoginsenoside-F11 alleviates cognitive deficits and Alzheimer's disease-type pathologies in SAMP8 mice.

Alzheimer's disease (AD) is a common neurodegenerative disease which is characterized by aggregation of amyloid beta (Aβ) and hyperphosphorylated tau. We previously reported that pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, improved cognitive function and reduced Aβ aggregation in APP/PS1 mice, a familial AD model. Here, we chose senescence-accelerated mouse prone 8 (SAMP8) mice, a widely used model of aging, to investigate the effect of PF11 on sporadic AD. PF11 was orally administered to male 6-month-old SAMP8 mice for 3 months. Consistent with previous studies, SAMP8 mice showed several AD-type pathologies including cognitive impairment, Aβ deposition and tau hyperphosphorylation. We found increased protein levels of cytoplasmic amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) in the hippocampus and cortex of SAMP8 mice. The protein level of demethylated protein phosphatase 2A (PP2A) was elevated in SAMP8 animals and the protein level of leucine carboxyl methyltransferase 1 (LCMT-1) was reduced. PF11 attenuated learning and memory impairments in the novel object recognition test and Morris water maze. PF11 promoted the transport of APP from cytoplasm to plasma membrane and decreased the abnormally high expression of BACE1 in hippocampus and cortex of SAMP8 mice. The elevated protein level of demethylated PP2A and the reduced expression of LCMT-1 in hippocampus and cortex of SAMP8 were also attenuated by PF11. Together, our findings indicate that PF11 has beneficial effects on AD-like pathological changes in SAMP8 mice and may act by inhibiting amyloidogenic processing of APP and attenuating tau hyperphosphorylation.

Carbohydrate-restricted diet promotes skin senescence in senescence-accelerated prone mice.

This study used senescence-accelerated prone mice (SAMP8) to examine the effects of a carbohydrate-restricted diet on aging and skin senescence, to determine how long-term carbohydrate restriction affects the aging process. Three-week-old male SAMP8 mice were divided into three groups after 1week of preliminary feeding: one was given a controlled diet, the other was given a high-fat diet, and the third was given a carbohydrate-restricted diet. Ad libitum feeding was administered until the mice reached 50weeks of age. Before the end of the test period, a grading test was used to evaluate visible aging in the mice. After the test period, serum and skin samples in mice were obtained and submitted for analysis. As a result, the grading test demonstrated that there was significant progression of visible aging in the carbohydrate-restricted group, as well as a decreased survival rate. Histological examination of the skin revealed that the epidermis and dermis in the carbohydrate-restricted group had become thinner. Analysis of the mechanisms involved demonstrated an increase in serum interleukin-6, aggravated skin senescence, inhibition of skin autophagy and activation of skin mTOR. Therefore, this study proved that a carbohydrate-restricted diet promoted skin senescence in senescence-accelerated mice.

Tempeh attenuates cognitive deficit, antioxidant imbalance, and amyloid β of senescence-accelerated mice by modulating Nrf2 expression via MAPK pathway

This study investigated the effects of tempeh on the cognitive and antioxidant status in senescence-accelerated mouse prone 8 (SAMP8) mice. Six-month-old SAMP8 mice were divided into one control and three tempeh groups; the tempeh groups were administered 300, 600, and 900 mg/kg body weight (BW) tempeh. The results revealed tempeh groups had stronger cognitive ability, lower malondialdehyde and carbonyl protein levels, and higher superoxide dismutase (SOD) and catalase (CAT) activities in the hippocampus, striatum, and cortex. Of them, the 900 mg/kg BW tempeh showed the most superior results on increasing SOD and CAT mRNA expressions and reducing amyloid β (Aβ) and β-site amyloid precursor protein cleaving enzyme 1 levels; it also increased nuclear factor erythroid 2-related factor 2 (Nrf2) levels by reducing p-p38 and p-JNK expression. In conclusion, tempeh may protect neurons against oxidative stress and Aβ-induced damage and reduce memory impairment by modulating Nrf2 via mitogen-activated protein kinase pathway.

Chronic noise exposure exacerbates AD-like neuropathology in SAMP8 mice in relation to Wnt signaling in the PFC and hippocampus

Non-genetic environmental hazards are thought to be associated with genetic susceptibility factors that increase Alzheimer’s disease (AD) pathogenesis. Aging and chronic noise exposure have been considered important factors in the AD. Here, we investigated the impact of chronic noise exposure on the AD-like neuropathology in the senescence-accelerated prone mouse (SAMP8) and the underlying mechanisms of such effects. We examined the consequences of AD-like neuropathology in 3-month-old SAMP8 mice using low- and high-intensity noise exposure and 8-month-old SAMP8 mice as aging positive controls. Immunoblotting and immunohistochemistry were conducted to examine AD-like pathological changes and potential mechanisms. Chronic noise exposure led to progressive overproduction of Aβ and increased the hyperphosphorylation of tau at Ser396, Thr205, and Thr231 sites in the hippocampus and the prefrontal cortex (PFC) in young SAMP8 mice, similar to that observed in aging SAMP8 mice. Both noise exposure and aging could cause a significant downregulation in Wnt signaling expression. These findings demonstrate that chronic noise stress exacerbated AD-like neuropathology, possibly by disrupting Wnt signaling and triggering aberrant tau hyperphosphorylation and Aβ in the PFC and hippocampus.

Yokukansan Ameliorates Hippocampus-Dependent Learning Impairment in Senescence-Accelerated Mouse.

Yokukansan (YKS) is a traditional Japanese herbal medicine. It has been currently applied for treating behavioral and psychological symptoms of dementia in Japan. We investigated the effect of YKS on learning ability, hippocampal cell proliferation, and neural ultrastructural features in senescence-accelerated mouse prone 8 (SAMP8), a proposed animal model of Alzheimer's disease. Five-month-old male SAMP8 mice were randomly assigned to control and experimental groups. The control group had drug-free water ad libitum. The experimental mice were given 0.15% aqueous solution of YKS orally for eight weeks. Learning ability was assessed in Morris water maze test. Hippocampal cell proliferation was investigated using bromodeoxyuridine immunohistochemical method. The neural ultrastructural features, including myelin sheath and synapse, were investigated electron microscopy. Administration with YKS improved the hippocampal cell proliferation in dentate gyrus, and ameliorated learning impairment in SAMP8 mice. Numerous lipofuscin inclusions were presented in hippocampal neurons of the control mice. However, little were found after treatment with YKS. Myelin sheath was thicker and postsynaptic density length was longer after treatment with YKS. Administration with YKS ameliorated learning impairment in SAMP8 mice, mediated at least partially via delaying neuronal aging process, neurogenesis, myelin sheath and synaptic plasticity in the hippocampus. These results suggest that YKS might be effective for preventing hippocampus-dependent cognitive deficits with age.

Dendrobium polysaccharides attenuate cognitive impairment in senescence-accelerated mouse prone 8 mice via modulation of microglial activation

Dendrobium is one of the most important traditional Chinese medicinal foods used to treat age-related disorders. However, it remains unclear whether Dendrobium affects the progression of Alzheimer’s disease (AD). In the present study, we investigated the effects of Dendrobium officinale polysaccharides (DOP) on the BV2 microglial cell line and the senescence-accelerated mouse prone 8 (SAMP8) mouse strain. In vitro experiments showed that DOP pretreatment contributed to BV2 cells shifting from proinflammatory to anti-inflammatory phenotypes with enhanced Aβ clearance in response to Aβ insults. For the in vivo study, mice were chronically treated with DOP in drinking water from 4 to 7 months of age. The results showed that DOP remarkably attenuated cognitive decline in SAMP8 mice. DOP also inhibited the increased hippocampal microglial activation in SAMP8 mice with downregulation of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), while interleukin-10 (IL-10), neprilysin (NEP) and insulin-degrading enzyme (IDE) were upregulated. The accumulation of hippocampal Aβ42 and phosphated Tau proteins in SAMP8 mice was also reduced. Taken together, our data suggest that Dendrobium has the potential to provide neuroprotection against AD-related cognitive impairment via modulation of microglial activation.