Brain Of Senescence-accelerated Mouse Research Articles

Observation of Acupuncture Effects on the Expression of Taurine Transporter and Taurine in the Senescence-Accelerated Mouse Brain: A Pilot Study.

In living organisms, taurine is important for homeostasis and is known to have preventive and inhibitory effects on various diseases. Taurine has been reported to play an important role in the development of the brain in newborns and in reducing the damage caused by cerebral ischemia. Previous studies indicated that acupuncture on a pair of acupoints of "DU16" and "DU20" can increase brain taurine transporter (TauT) expression in mice with penicillin-induced epilepsy and enhanced taurine anti-epilepsy effects. Our previous study reported that manual acupuncture stimulation of the head acupuncture points "Bai-Hui" (GV 20) and "Yintang" (Ex-HN3) could produce antidepressant effects. In this study, we investigated whether acupuncture stimulation of the head acupuncture points GV 20 and Ex-HN3 affects the expression of TauT and taurine in the cerebellum and hippocampus in senescence-accelerated mice. Acupuncture stimulation significantly increased the mRNA expression of TauT in the cerebellum and hippocampus. Immunohistochemical staining confirmed that the expression of TauT and taurine in the cerebellum and hippocampus increased. These results indicate that acupuncture stimulation might improve cognitive and behavioral abilities by increasing the expression of TauT and taurine.

Aging alters lipid mediator biosynthesis from polyunsaturated fatty acids in the brain of senescence-accelerated mice with age-related cognitive dysfunction

Aging alters lipid mediator biosynthesis from polyunsaturated fatty acids in the brain of senescence-accelerated mice with age-related cognitive dysfunction

ROLES OF AMPK IN THE TAU PHOSPHORYLATION IN THE BRAIN OF SENESCENCE-ACCELERATED MICE

ROLES OF AMPK IN THE TAU PHOSPHORYLATION IN THE BRAIN OF SENESCENCE-ACCELERATED MICE

Resveratrol attenuates oxidative damage and ameliorates cognitive impairment in the brain of senescence-accelerated mice

AimsResveratrol (Res) which is a polyphenolic phytoalexin, has various biological properties. In the present study, we investigated whether Res extracted from Polygonum cuspidatum can reduce oxidative damage and cognitive impairment in senescence-accelerated mouse (SAM). Main methodsSenescence-accelerated mice were administered with Res (25, 50, 100mg·kg−1·d−1) for 8weeks. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) in mice brain were determined. The gene expression of SOD in mice brain was investigated by real time reverse transcriptase‐polymerase chain reaction (RT-PCR). Key findingsThe results showed that resveratrol significantly improved learning and memory ability in Morris water maze test and neuromuscular coordination and sensorimotor capacity in tightrope test. Meanwhile, Res increased the activities of antioxidant enzymes with a reduction in lipid peroxidation. And real time RT-PCR analysis also indicated that the change of SOD mRNA was the same as the modification of SOD activity in mice brain. Furthermore, Res could prevent cerebral mitochondrial DNA deletions which might be one of the causes resulting in learning and memory impairment. SignificanceThese results suggest that the pharmacological action of Res may offer a novel therapeutic strategy for the treatment of age-related conditions.

The Activity and mRNA Expression of β-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-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.

Beta-Cryptoxanthin, Plentiful in Japanese Mandarin Orange, Prevents Age-Related Cognitive Dysfunction and Oxidative Damage in Senescence-Accelerated Mouse Brain

Increased oxidative stress is known to accelerate age-related pathologies. Beta-cryptoxanthin (β-CRX, (3R)-β,β-caroten-3-ol) is a potent antioxidant that is highly rich in Satsuma mandarin orange (mandarin), which is the most popular fruit in Japan. We investigated the antioxidative and anti-aging effects of β-CRX and mandarin using senescence-accelerated mice (SAMP10), which were characterized by a short lifespan, high generation of superoxide anions in the brain and poor learning ability with aging. β-CRX (0.5-5.0 µg/ml) or mandarin juice (3.8-38.0%) was added to drinking water of SAMP10 one to 12 months of age. β-CRX was dose-dependently incorporated into the cerebral cortex and the contents were similar to the concentration of β-CRX in the human frontal lobe. These mice also had higher learning ability. The level of DNA oxidative damage was significantly lower in the cerebral cortex of mice that ingested β-CRX and mandarin than control mice. In addition, the mice that ingested β-CRX (>1.5 µg/ml) and mandarin (>11.3%) exhibited a higher survival when 12 month-old, the presenile age of SAMP10, than control mice. These results suggest that β-CRX is incorporated into the brain and has an important antioxidative role and anti-aging effect.

Elevated Oxidative Stress in the Brain of Senescence-accelerated Mice at 5 Months of Age

The senescence-accelerated mouse (SAM) is a useful animal model to study aging or age-associated disorder. In the present study, we have used a multidisciplinary approach to the characterization of changes that occur in aging and in the modelling of brain aging. The SAMP8 mouse at 5 months of age exhibited an increase in gliosis and molecular oxidative damage. Likewise, we found that superoxide dismutase activity decreased compared with age-matched SAMR1 while there were no differences in activity of catalase and glutathione reductase. These results indicate that the decrease of superoxide dismutase may be involved in the increase of oxidative stress in brain of SAMP8 at younger stages. This suggestion is supported by an increase in the expression of alpha-synuclein together with phosphorylated tau protein, which is concurrent with the decline of that antioxidant enzyme. Alpha-synuclein aggregates are invariably associated with tau pathologies and our results demonstrate that alpha-synuclein accumulation is a potent inducer of tau pathologies not only in neurodegenerative diseases but also in normal aging. These results also imply that SAMP8 are exposed to elevated levels of oxidative stress from an early age, and that could be a very important cause of the senescence-related impairments and degeneration in the brain seen in this strain.

Changes of Metallothionein 1 and 3 mRNA Levels with Age in Brain of Senescence-Accelerated Mice and The Effects of Acupuncture

The effects of aging and acupuncture on brain MT1 and MT3 mRNA levels in senescence-accelerated mice (SAMP10) and accelerated senescence resistant mice (SAMR1) were analyzed by Northern blot analysis. Both MT1 and MT3 mRNA levels in SAMR1 were increased significantly from birth to month 4 and decreased gradually thereafter. In SAMP10, the MT3 mRNA level followed the same pattern as in SAMR1 before month 4, then decreased from month 4 to 6, but was over-expressed and exceeded the previous level at month 8. The MT1 mRNA expression in SAMP10 showed a zigzag pattern. Of two groups of SAMP10 mice treated with acupuncture, the xingnao group (PC6 and Du26 as acupoints) and the zibuganshen group (BL18 and BL23 as acupoints), both showed a higher MT1 mRNA level and a lower MT3 mRNA level than the age-matched control group. Meanwhile, in both of the acupuncture groups, the ratios of MT3 to MT1 were down-regulated to the normal range. Overall, these results suggested that over-expression of MT3 mRNA and the increase in MT3 to MT1 ratios in SAMP10 were correlated with aging, and could be an important physiological and pathological event in the aging process. Acupuncture altered the expression levels of MT1 and MT3 mRNA and differences between the effects of the two stimulated acupoints were seen. Therefore, maintenance of the balance between MTs mRNA expression and correct MTs concentrations is crucial for brain-endocrine-immune response and normal aging. Acupuncture could improve zinc ion bioavailability, by maintaining the balance between MT1 and MT3 mRNA expression levels and might explain one of the mechanisms by which acupuncture treatments defer aging and treat some age-related neurodegenerative diseases.

Alteration of Leptin-Induced STAT3 Activation in the Brain of Senescence-Accelerated Mouse (SAM) P8

We used senescence-accelerated mouse prone 8 (SAMP8), a useful model of accelerated aging, to investigate the responsiveness to leptin with aging. The state of leptin-induced STAT3 phosphorylation in the hypothalamus was found to be higher in SAMP8 than in SAMR1, a control mouse showing normal aging, at 14-18 months of age but not at 2 months of age. Moreover, leptin receptor Ob-Rb expression in the hypothalamus was up-regulated in SAMP8. The results indicate that leptin sensitivity increases with aging in the SAM mouse brain.

Age-Related Alterations in the Expression of Glial Cell Line-Derived Neurotrophic Factor in the Senescence-Accelerated Mouse Brain

Age-Related Alterations in the Expression of Glial Cell Line-Derived Neurotrophic Factor in the Senescence-Accelerated Mouse Brain

Analysis of the expression of endogenous murine leukemia viruses in the brains of senescence-accelerated mice (SAMP8) and the relationship between expression and brain histopathology.

Many studies have explored the premature aging of accelerated senescence-prone (SAMP8) mice. However, the cause of premature aging in this strain remains unknown. We analyzed the expression of ecotropic, xenotropic, and polytropic murine leukemia viruses (MuLVs) in the brains of accelerated senescence-resistant (SAMR1) and SAMP8 mice. No ecotropic mRNA was detected in SAMR1 mice, and only Akv-type ecotropic MuLV mRNA was detected in SAMP8 mice. Restriction mapping of the full-length infectious E-MuLV genome from SAMP8 confirmed its identity as Akv. mRNAs corresponding to a prototypical polytropic MuLV and to an unusual xenotropic MuLV were detected at equal levels in SAMP8 and SAMR1 mice, but no infectious virus of either host range type was detected. In order to determine the cellular localization of Akv expression in SAMP8 mice, we used immunohistochemistry and electron microscopy to detect expression of the E-MuLV capsid gag (CAgag) gene in striatum, brainstem, hippocampus, and cerebellum of 12-month-old SAMR1 and SAMP8 mice. The CAgag antigen was seen in the neurons, oligodendroglia, and vascular endothelium of these brain regions of SAMP8 mice, but not in SAMR1 mice. To evaluate the correlation between activation of astrocytes and expression of Akv, we performed double-immunohistochemical staining for both glial fibrillary acidic protein (GFAP) and CAgag in SAMR1 and SAMP8 mice. Strong astrocytic activation and extensive vacuolation were observed around CAgag-positive neurons in SAMP8 mice, whereas in SAMR1 mice neither astrocytosis nor vacuolation were present. CAgag antigen was also localized in astrocytes of the hippocampus region of SAMP8 mice. Electron micrography showed that a number of vacuoles were found in the cytoplasm of MuLV-positive neurons and the extracellular space surrounding these neurons showed lytic changes. These results suggest that endogenous Akv provirus is expressed in neurons, astrocytes, vascular endothelium, and oligodendroglia in the brains of SAMP8 and that this virus could play an important role in the brain aging processes in this mouse strain.

Melatonin reduces oxidative damage of neural lipids and proteins in senescence-accelerated mouse.

We investigated whether long-term melatonin administration in the drinking water influences oxidative modification of lipids and proteins and antioxidative enzyme activity in brain of senescence-accelerated mice (SAM). Cerebral cortex was obtained in the middle of the dark period of the daily light cycle from SAMP8, a strain of mice prone to accelerated senescence, and from SAMR1, a senescence-resistant strain, at 3, 6, and 12 months of age. Thiobarbituric acid-reactive substances (TBARS) and protein carbonyls exhibited significant age-related increases in both strains. Glutathione peroxidase (GPx) activity decreased significantly at 12 months of age in SAMP8. No age effect was found in GPx activity in SAMR1, or in superoxide dismutase (SOD) activity in either strain. Melatonin administration (2 microg/mL) via the drinking fluid beginning at 7 months significantly decreased neural TBARS content (over 30%) in both strains and lowered the protein carbonyl content in the brain of SAMP8 mice. Furthermore, melatonin significantly augmented GPx activity (over 20%) in both strains. Melatonin had no effect on SOD activity. These results suggest an age-related increase in cerebral tissue vulnerability to oxidation in SAM that can be modified by melatonin, most likely through the ability of melatonin to scavenge oxygen free radicals and to stimulate antioxidant enzyme activity.

Learning behaviour and cerebral protein kinase C, antioxidant status, lipid composition in senescence-accelerated mouse: influence of a phosphatidylcholine–vitamin B12diet

Our objective was to determine whether dietary supplementation with phosphatidylcholine (PC) plus vitamin B12 could afford beneficial effects on biochemical and biophysical events in the brain of senescence-accelerated mouse (SAM) substrain SAMP8. We measured learning behaviour, hippocampal protein kinase C (PKC) activity, cerebral antioxidant status, phospholipid composition and fatty acid composition in 6-month-old SAMP8 and in age-matched controls (SAM substrain SAMR1). In comparison with SAMR1, SAMP8 showed a significant elevation in total grading score of senescence and a significant decline in acquisition SAMP8 had a lower hippocampal PKC activity and cerebral PKC-beta mRNA abundance than SAMR1. SAMP8 had increased cerebral lipid peroxide levels and proportion of sphingomyelin, and a lower proportion of 20 : 4n-6 and 22 : 6n-3 in cerebral phosphtidylethanolamine than SAMR1. SAMP8 fed the PC combined with vitamin B12 diet had an increased PKC activity and a higher proportion of 22 : 6n-3 than SAMP8 fed the control diet. These results indicate the potential benefit of PC combined with vitamin B12 as a dietary supplement.

Electrophoretic analyses of glutamate decarboxylase 67 kDa isoform and extracellular regulated kinase isozyme-2 in brains of senescence accelerated mice, SAM-P8.

Electrophoretic analyses of glutamate decarboxylase 67 kDa isoform and extracellular regulated kinase isozyme-2 in brains of senescence accelerated mice, SAM-P8.

Learning deficiency and alterations in acetylcholine receptors and protein kinase C in the brain of senescence-accelerated mouse (SAM)-P10

The senescence-accelerated mouse (SAM) is known to be a murine model for accelerated aging. A novel inbred SAMP10 has shown age-related brain atrophy and learning deficiency. In the present study, we investigated the changes in learning ability and in ligand binding with muscarinic acetylcholine (mACh) receptors, α adrenoceptors and protein kinase C in SAMP10. In Morris’s water maze task, in a control strain of SAMR1 at 9 months, the escape latency and path length decreased with increasing trial days, in contrast, escape latency and path length did not decrease in SAMP10. These results indicate that SAMP10 exhibits learning deficiency. The ligand binding activity of mACh receptors decreased in the hippocampus of SAMP10 and the protein kinase C level in the hippocampus of SAMP10 was lower than that of SAMR1. On the other hand, there was no significant difference between SAMR1 and SAMP10 regarding ligand binding activity of α 1 and α 2 adrenoceptors. Thus, a reduction of mACh receptors and protein kinase C in the brain seems to underlie dysfunction of learning and memory in SAMP10.

Alzheimer's disease-related gene expression in the brain of senescence accelerated mouse

The levels of Alzheimer's disease (AD)-related genes, including β-amyloid precursor protein(APP), presenilin-1 (PS-1), PS-2, apoE, tau, c-fos, neural cell adhesion molecular 180 (NCAM-180), TGF-β1, IL-1α/β, IL-6, TNF-α/β, α-2-Macroglobulin (α2M), class II major histocompatibility antigen Ia (MHCII Ia), bcl-2α, glucocorticoid receptor-α (GRα) and mineralocorticoid receptor (MR) mRNAs were determined by reverse transcription polymerase chain reaction (RT-PCR) in the hippocampus and cerebral cortex of senescence accelerated mouse (SAM). The levels of TGF-β1, IL-1α, TNF-β, c-fos, NCAM-180, PS-1 and APP mRNAs were normally expressed in SAMP8 compared with age-matched other subline that is resistant (SAMR1). The levels of apoE, GRα and MR mRNAs in the hippocampus of SAMP8, especially GRα, were evidently lower than those in the hippocampus of SAMR1. While bcl-2α, PS-2 and tau mRNA levels of SAMP8 were significantly higher than those of SAMR1. Inflammatory cytokines (IL-1β, IL-6, TNF-α), α2M and MHCII Ia antigen mRNAs were not detected in the brain of SAM. The differences of gene expression in the cerebral cortex were less evident than in the hippocampus. The results indicated that some genes abnormally expressed in the AD brain were also found in the brain of SAMP8, which may contribute to its age-related deterioration of learning and memory. Our results also suggested that functional and pathological changes which occurred in the brain of SAMP8 possessed some different aspects in comparison with the AD in consideration of the differences in gene expression.

Age-related changes in the brains of senescence-accelerated mice (SAM): association with glial and endothelial reactions.

Twelve substrains of inbred senescence-accelerated mice (SAM) have been developed, among which the SAMP8 and SAMP10 strains show a significant age-related deterioration in learning and memory for passive and active avoidance tasks. These strains have, respectively, a low and high incidence of systemic senile amyloidosis. Although we found no amyloid deposits in their brain parenchyma, a variety of age-related alterations were identified, involving neurons, glia, and vessels in the brain tissues. Here we review the degenerative changes in aged SAMP8 and SAMP10 brains. These changes are generally similar to the pathology of aging human brain and may be characterized by their association with some specific glial reactions.

Age-related increase in nitric oxide synthase activity in senescence accelerated mouse brain and the effect of long-term administration of superoxide radical scavenger

The levels of nitric oxide (NO) and NO synthase (NOS) activities were compared in the brains of young adult (3 months old), aged (11 months old) and TJ-960 administered (11 months old) senescence accelerated mice (SAM), of which the SAMP8 substrain is inferior in acquisition of learning due to the abnormality of glutamatergic neurotransmission in the cerebral cortex. TJ-960, which is based on the Kampo (Japanese traditional herbal medicine) prescription Sho-saiko-to-go-keishi-ka-shakuyaku-to, acts as a superoxide radical scavenger and attenuates the deterioration of neuronal activity associated with aging. We administered TJ-960 orally for 5 months. In the cerebral cortex of aged SAMP8, NOS activity was increased compared with that of young adult SAMP8. Though TJ-960 did not alter the contents of NO in any brain region compared with those in aged SAMP8, it did prevent the increase in NOS activity in the aged cerebral cortex. Our data suggest that NOS activity may increase to compensate for the reduced sensitivity of the NO reaction system in the aging process, and that TJ-960 may normalize this increased NOS activity in the cerebral cortex, although further work is clearly needed to ascertain maintenance in the acquisition of learning.

Age-related changes of mRNA expression of amyloid precursor protein in the brain of senescence-accelerated mouse

APP695 mRNA is only expressed in the brains of SAM. The expression of APP mRNA in SAM P1 mice brains is more marked than that in SAM R1 mice brain. APP mRNA expression was increased with advancing age in all brain regions of SAM P1 mice compared with SAM R1. Especially, the changes of the amount of APP mRNA in the prosencephalon and the mesencephalon are significant at P value of 0.05. We suggest that overexpression of APP mRNA may be related to accelerated aging phenomenon in the SAM brain. This is the first report of age-related increase in the amount of APP mRNA in the SAM brain.

Neurochemical changes related to ageing in the senescence-accelerated mouse brain and the effect of chronic administration of nimodipine

The levels of neurotransmitters and related metabolic enzyme activities in the brain of young-adult (3 months old), aged (11 months old) and nimodipine-administered (11 months old) senescence-accelerated mouse (SAM) were compared. Nimodipine, a calcium antagonist, was administered orally for 5 months. Acetylcholine (ACh), serotonin (5-HT) and dopamine (DA) levels all decreased with age but this decrease was attenuated by nimodipine. Choline acetyltransferase and choline esterase activities increased with age, and nimodipine enhanced their activities. Tryptophan hydroxylase activity was not affected by age or nimodipine administration. Monoamine oxidase-A activity increased with age, and was decreased by nimodipine administration. These results suggest that SAM rapidly undergoes neurochemical changes which are considered to be part of the normal aging process, and these changes were attenuated by chronic administration of nimodipine.