Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Zinc finger protein 521 (ZFP521) regulates a number of cellular processes in a wide range of tissues, such as osteoblast formation and adipose commitment and differentiation. In the field of neurobiology, it is reported to be an essential factor for transition of epiblast stem cells into neural progenitors in vitro. However, the role of ZFP521 in the brain in vivo still remains elusive. To elucidate the role of ZFP521 in the mouse brain, we generated mice lacking exon 4 of the ZFP521 gene. The birth ratio of our ZFP521(Delta/Delta) mice was consistent with Mendel's laws. Although ZFP521(Delta/Delta) pups had no apparent defect in the body and were indistinguishable from ZFP521(+/+) and ZFP521(+/Delta) littermates at the time of birth, ZFP521(Delta/Delta) mice displayed significant weight reduction as they grew, and most of them died before 10 weeks of age. They displayed abnormal behavior, such as hyper-locomotion, lower anxiety and impaired learning, which correspond to the symptoms of schizophrenia. The border of the granular cell layer of the dentate gyrus in the hippocampus of the mice was indistinct and granular neurons were reduced in number. Furthermore, Sox1-positive neural progenitor cells in the dentate gyrus and cerebellum were significantly reduced in number. Taken together, these findings indicate that ZFP521 directly or indirectly affects the formation of the neuronal cell layers of the dentate gyrus in the hippocampus, and thus ZFP521(Delta/Delta) mice displayed schizophrenia-relevant symptoms. ZFP521(Delta/Delta) mice may be a useful research tool as an animal model of schizophrenia.

DOI： 10.1371/journal.pone.0092848

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Aims: STAT3 is a key modulator of activation and differentiation of macrophages. But it is still unknown if deficiency of STAT3 activates macrophages to destroy erythrocytes by phagocytosis. We generated STAT3 conditional knockout mice by crossing foxed STAT3 mice with Tie2 promoter-driven Cre-recombinase transgenic mice and clarified that Stat3 plays a critical role in the formation and activation of macrophages.
Main methods: Blood cell count, reticulocyte count, serum lactate dehydrogenase, erythropoietin, iron and ferritin concentration, and life span of the erythrocytes in Tie2 promoter-driven STAT3 conditional knockout mice were analyzed. To explore the erythropoietic function of the mice, we subjected them to brief hemolytic anemia by injecting them intraperitoneally with phenylhydrazine. The fragility of erythrocytes was examined by scanning electron microscopy and osmotic tolerance test.
Key findings: The conditional knockout mice had mild normocytic anemia. They also displayed higher lactate dehydrogenase, ferritin and erythropoietin concentration, higher reticulocyte count, and a shorter lifespan of erythrocytes compared with wild-type controls. These data suggest that destruction of erythrocytes and secondary blood formation were accelerated in the STAT3 conditional knockout mice. It didn't appear due to the fragility of erythrocytes. A few of the conditional knockout mice suddenly developed acute severe anemia, high body temperature and massive splenomegaly, and died within 2 weeks after the onset of anemia.
Significance: This study provided evidence that STAT3 have a critical role in the destruction of erythrocytes by resident macrophages in the spleen. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.lfs.2013.07.025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The mechanisms of cell death induced by hypoxia or ischemia are not yet fully understood. We have previously demonstrated that cell death induced by hypoxia occurs independently of caspases, and is mediated by phospholipase A(2) (PLA(2)).
Here, we show that p38 mitogen-activated protein kinase is activated under hypoxia. A selective inhibitor of p38 or decrease in the p38alpha protein level prevents hypoxia-induced cell death. The p38 inhibitor abolishes PLA(2) activation by hypoxia, indicating that p38 acts upstream of PLA(2). The antioxidant N-acetyl-cysteine inhibits activation of p38 and cell death induced by hypoxia, indicating that reactive oxygen species (ROS) are responsible for p38 activation. These results demonstrate that the ROS/p38/PLA(2) signaling axis has a crucial role in caspase-independent cell death induced by hypoxia. Crown Copyright (C) 2009 Published by Elsevier B. V. on behalf of Federation of European Biochemical society. All rights reserved.

DOI： 10.1016/j.febslet.2009.04.028

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Disabled 1 (Dab1), a cytoplasmic adaptor protein expressed predominantly in the CNS, transduces a Reelin-initiated signaling that controls neuronal migration and positioning during brain development. To determine the role of Dab1 in neural stern cell (NSC) differentiation. we established a Culture of neurospheres derived from the embryonic forebrain of the Dab1(-/-) mice, yotari. Differentiating Dab1(-/-) neurospheres exhibited a higher expression of GFAP, an astrocytic marker, at the expense of neuronal markets. Under Dab1-deficient condition, the expression of NeuroD, a transcription factor for neuronal differentiation, was decreased and the JAK-STAT pathway was evidently increased during differentiation of NSC, suggesting the possible involvement of Dab1 in astrocyte differentiation via JAK-STAT pathway. Notably, expression of neural and glial markers and the level of JAK-STAT signaling molecules were not changed in differentiating NSC by Reelin treatment, indicating that differentiation of NSC is Reelin-independent. Immunohistochemical analyses showed a decrease in the number of neurons and an increase in the number of GFAP-positive cells in developing yotari brains. Our results suggest that Dab1 participates in the differentiation of NSCs into a specific cell lineage, thereby maintaining a balance between neurogenesis and gliogenesis. (C) 2008 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.mcn.2008.08.012

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Language：English   Publisher：SPRINGER TOKYO  

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Language：English   Publisher：SPRINGER TOKYO  

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Language：English   Publisher：SPRINGER TOKYO  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOS PRESS  

The extract from Panax ginseng has been reported to improve the microcirculation in various organs. However, the mechanisms underlying this phenomenon are still poorly understood. In the present study, using the rheological properties of erythrocytes as an index, we have screened the components of Panax ginseng extract and identified Rg(2) and Rh-1 as the active ingredients. These two ginsenosides prevented the oxidative stress-induced elevation of erythrocyte suspension viscosity and the impairment of erythrocyte elongation in response to shear stress. Rg2 and Rh1 ginsenosides did not have antioxidant activity in an aqueous phase and did not inhibit the peroxidation of membrane lipids, either. However, they inhibited the oxidation-induced decrease of SH-groups in band 3 (anion exchanger-1), one of the important structural proteins of the erythrocyte membrane, but not in other structural proteins: bands 1 and 2 (spectrins), band 4.2 or band 5 (actin). These results suggest that ginsenosides Rg2 and Rh1 protect the rheological functions of erythrocytes against oxidative stress by preventing the oxidation of SH-groups in band 3 protein.

DOI： 10.3233/BIR-2008-0516

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Reelin plays an important role in the migration of embryonic neurons, but its continuing presence suggests additional functions in the brain. We now report a novel function where reelin protects P19 embryonal cells from apoptosis during retinoic acid-induced neuronal differentiation. This increased survival is associated with reelin activation of the phosphatidyl-inositol-3-kinase (P13 K)/Akt pathway. When P13 K was inhibited with LY294002, reelin failed to protect against this retinoic acid-induced apoptosis. The protective effect of reelin includes activating the Src-family kinases/P13 K/Akt pathway which then led to selective phosphorylation of Bcl-2/Bcl-XL associated death promoter (BAD) at serine-136, while the phosphorylation-incompetent mutation of BAD (S136A) suppressed this protection. These and additional studies define a novel pathway where reelin binds apoE receptors, significantly activates the P13 K/Akt pathway causing phosphorylation of BAD which helps to protect cells from apoptosing, thus serving an important role in promoting the survival of maturing neurons in the brain.

DOI： 10.1111/j.1471-4159.2007.04804.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Red ginseng root (Panax Ginseng CA Meyer) has been used clinically by many Asian people for thousands of years without any detrimental effects. One of the major components of Red ginseng root is ginsenoside Rb-1 (gRb1). Previously, we showed that intravenous infusion of gRb1 ameliorated ischemic brain damage through upregulation of an anti-apoptotic factor, BCI-X-L and that topical application of gRb1 to burn wound lesion facilitated wound healing through upregulation of vascular endothelial growth factor (VEGF). In the present study, we produced dihydroginsenoside Rb1 (dgRb1), a stable chemical derivative of gRb1, and showed that intravenous infusion of dgRb1 improved spinal cord injury (SCI) as well as ischemic brain damage. As we expected, the effective dose of dgRb1 was ten times lower than that of gRb1. Intravenous infusion of dgRb1 at this effective dose did not affect brain temperature, blood pressure or cerebral blood flow, suggesting that dgRb1 rescued damaged neurons without affecting systemic parameters. In subsequent in vitro studies that focused on dgRb1-induced expression of gene products responsible for neuronal death or survival, we showed that dgRb1 could upregulate the expression of not only BCI-XL, but also a potent angiogenic and neurotrophic factor, VEGF. We also showed that dgRb1-induced expression of bcl-X-L and VEGF mRNA was HRE (hypoxia response element) and STRE (signal transducers and activators of transcription 5 (Stat5) response element) dependent, respectively.

DOI： 10.1089/neu.2006.0182

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOS PRESS  

Erythrocytes are very susceptible to oxidative stress, having a high content of intracellular oxygen and hemoglobin. In the present study, exposure to oxidative stress resulted in a significant impairment of erythrocyte membrane functions, such as deformability and anion exchange. Band 3 protein, also known as anion exchanger-1, plays an important role in these two functions. We show that oxidative stress activated caspase-3 inside the erythrocytes, which resulted in band 3 protein cleavage. Interestingly, inhibition of the caspase-3 with its specific inhibitor not only suppressed the digestion of band 3 protein, but also blunted the functional damage to erythrocytes, such as deformability and anion exchange, without changing the level of peroxidation of membrane lipids. These results provide experimental evidence that activation of caspase-3 plays an important role in the oxidative stress-induced impairment of membrane functions of erythrocytes.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

Significant differences exist in the production and release of nitric oxide (NO) from human macrophages versus macrophages of mouse origin. Human macrophages have been shown to respond poorly to stimuli that provoke strong inflammatory reactions from mouse macrophages. To address the differences in macrophage function in an animal model, a transgenic mouse was created that contained the entire human NOS2 gene, including the human promoter and all of its exons and introns. The huNOS2 transgenic mouse was then mated to mice lacking a functional NOS2 gene (muNOS2(-/-) or NOS2 knockout mice) to generate a double transgenic mouse (huNOS2(+/0)/muNOS2(-/-)) that expresses a functional human NOS2 gene in place of the mouse NOS2 gene. These double transgenic mice were found to express only human NOS2 mRNA and human iNOS proteins in response to immune stimulation. The production and release of nitric oxide from isolated macrophages from the doubly transgenic mouse also more closely paralleled human responses rather than mouse. Peritoneal macrophages from double transgenic mice generated nanomolar levels of nitrite in response to inflammatory stimuli, while peritoneal macrophages from wild-type mice generated micromolar levels of nitrite in response to the same inflammatory stimuli. Similarly, microglia from the huNOS(2+/0)/muNOS2(-/-) mice accumulated nanomolar levels of nitrite following inflammatory stimulation. Reduced nitrite release persisted in spite of normal responsiveness to inflammatory stimulation as measured by tumor necrosis factor alpha and interleukin-6 production and release. These data suggest that the human-specific release of nanomolar levels of nitrite may largely result from differences between the human and mouse NOS2 genes, which may program different degrees of nitric oxide responses to inflammatory signals in humans than in mice.

DOI： 10.1089/ars.2006.8.893

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Almost all agents that exhibit neuroprotection when administered into the cerebral ventricles are ineffective or much less effective in rescuing damaged neurons when infused into the blood stream. Search for an intravenously infusible drug with a potent neuroprotective action is essential for the treatment of millions of patients suffering from acute brain diseases. Here, we report that postischemic intravenous infusion of a ginseng saponin, ginsenoside Rb-1 (gRb(1)) (C54H92O23, molecular weight 1109.46) to stroke-prone spontaneously hypertensive rats with permanent occlusion of the middle cerebral artery distal to the striate branches significantly ameliorated ischemia-induced place navigation disability and caused an approximately 50% decrease in the volume of the cortical infarct lesion in comparison with vehicle-infused ischemic controls. In subsequent studies that focused on gRb(1)-induced expression of gene products responsible for neuronal death or survival, we showed that gRb(1) stimulated the expression of the mitochondrion-associated antiapoptotic factor Bcl-x(L) in vitro and in vivo. Moreover, we revealed that a Stat5 responsive element in the bcl-x promoter became active in response to gRb(1) treatment. Ginsenoside Rb-1 appears to be a promising agent not only for the treatment of cerebral stroke, but also for the treatment of other diseases involving activation of mitochondrial cell death signaling.

DOI： 10.1038/sj.jcbfm.9600225

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrun in human brain tissue. This transcript (NCSTN-Delta E16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon 4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-Delta E16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-Delta E16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon 4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease. (c) 2005 Elsevier Inc All rights reserved.

DOI： 10.1016/j.lfs.2005.10.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

To investigate the effects of signal transducer and activator of transcription 3 (Stat3) on neural stem cell fate, stem cells were inoculated with an adenovirus vector expressing dominant negative form of Stat3 (Stat3F). One day later, a promoter assay revealed significant reduction of the transcriptional level in the transfected cells. Three days later, Western blot analysis and immunocytochemical analysis revealed that the protein level of microtubule-associated protein (MAP)2 and the number of MAP2-positive cells were increased significantly in the transfected cells whereas the protein level of glial fibrillary acidic protein (GFAP) and the number of GFAP-positive cells were decreased significantly. In addition, mRNA levels of Notch family members (Notch1, 2, and 3) and of inhibitory basic helix-loop-helix (bHLH) factors (Hes5, Id2, and Id3) were significantly downregulated at 3 days after viral inoculation with Stat3F; however, mRNA levels of bHLH determination factors (Math1 and Neurogenin3) and bHLH differentiation factors (NeuroD1 and NeuroD2) were significantly upregulated. These data indicated that suppression of Stat3 directly induced neurogenesis and inhibited astrogliogenesis in neural stem cells. (c) 2005 Wiley-Liss, Inc.

DOI： 10.1002/jnr.20561

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Language：Japanese   Publisher：日本生理学会  

Erythrocyte flow behavior in microvessels affects not only flow resistance, but also oxygen transfer to peripheral tissues. Erythrocytes flowing through a microvessel tend to accumulate in the central flow axis, and thus cell-free layer appears along inner wall of the vessel. The oxygen release from flowing erythrocytes was examined using an oxygen-permeable fluorinated ethylenepropylene copolymer tube (inner diameter, 0.027 mm). After exposing the narrow tube to deoxygenated environment, the oxygen saturation was measured with a spectrophotometer under a microscope. We modified the flow behavior of erythrocytes by applying accelerational force perpendicularly to the flow direction using a centrifuge or by perfusing erythrocytes reduced in sialic acid content of the membrane proteins with neuraminidase to decrease electrostatic interaction among erythrocytes.(1) With increasing the centifugal force, the oxygen release from flowing cells was suppressed accompanying the shift of the cell flow column to centrifugal side and the compression of the flow column.(2) With decreasing sialic acids of erythrocytes, oxygen release from cells was decreased, especially at low pH condition (pH=6.5). In conclusion, this research suggests that accumulation of flowing erythrocytes affects the oxygen diffusion from erythrocytes to tissue in microcirculation. <b>[Jpn J Physiol 55 Suppl:S90 (2005)]</b>

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Language：Japanese   Publisher：日本病態生理学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Apolipoprotein E (ApoE), one of the genetic risk factors for Alzheimer's disease, is considered to have a critical role in transporting lipids in the brain. In the present study, we investigated ApoE release in primary rat microglial cultures. Microglial cells released ApoE in response to L-Ser in culture medium, and ApoE-immunoreactivity was detected in granules in the cell periphery and in perinuclear structures. Immunocytochemical studies, immunoblotting, and reverse transcription-polymerase chain reaction (RT-PCR) results all supported the notion that microglial cells are the potential source of ApoE in the brain. L-Ser enhanced ApoE release in a concentration-dependent manner without upregulating ApoE mRNA expression. Astrocytes presumably enhanced production and release of ApoE by microglial cells through secretion Of L-Ser. As revealed by gel chromatography, ApoE was secreted as a component of lipoproteins, and L-Ser enhanced release of cholesterol and triglycerides together with ApoE. Activation of microglial cells by lipopolysaccharides and serum resulted in an overall decrease of the ApoE release. These findings suggest that microglial cells are a significant source of lipoproteins containing ApoE in the brain under physiological conditions, and that L-Ser is an important mediator of the neuron-astrocyte-microglia network in the brain. (C) 2003 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.expneurol.2003.10.010

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Vitamin E has been shown to have protective effects against cerebral ischemia, possibly due to its antioxidant effects. However, its non-anti-oxidant, intracellular molecular mechanism remains elusive. For in vivo experiments in rats, orally administered vitamin E significantly reduced not only the brain infarct volume but also space navigation disability after permanent middle cerebral artery (MCA) occlusion. The level of anti-oxidant after MCA occlusion was significantly increased specifically in the ipsilateral brain tissues of vitamin E-treated rats. For in vitro experiments, posttreatment with vitamin E protected primary cultured neurons from nitric oxide-induced insult. Vitamin E induced the expression of the a subunit of hypoxia-inducible factor-1 (HIF-1) and its target genes, including vascular endothelial growth factor (VEGF) and heme oxygenase-1. The hypoxia response element on the VEGF promoter was responsible for this vitamin E-induced transcriptional activation of VEGF gene. Taken together, these results suggest that cerebral infarction increased the permeability of vitamin E across the blood-brain barrier, and this increased vitamin E in brain tissue elicited neuroprotective effects not only through scavenging oxidants, as are previously well reported, but also by transactivating HIF-1-dependent genes, which results in protection of brains from ischemic insults. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.neuroscience.2004.03.057

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The levels of plasma HDL cholesterol and apoA-I in NFkappaB p50 subunit-deficient mice were significantly higher than those in wild-type mice under regular and high fat diets, without any significant difference in the level of total cholesterol. To examine the role of NFkappaB in lipid metabolism, we studied its effect on the regulation of apoA-I secretion from human hepatoma HepG2 cells. Lipopolysaccharide-induced activation of NFkappaB reduced the expression of apoA-I mRNA and protein, whereas adenovirus-mediated expression of IkappaBalpha super-repressor ameliorated the reduction. This IkappaBalpha-induced apoA-I increase was blocked by preincubation with MK886, a selective inhibitor of peroxisome proliferator-activated receptor alpha (PPARalpha), suggesting that NFkappaB inactivation induces apoA-I through activation of PPARalpha. To further support this idea, the expression of IkappaBalpha increased apoA-I promoter activity, and this increase was blocked by preincubation with MK886. Mutations in the putative PPARalpha-binding site in the apoA-I promoter or lack of the site abrogated these changes. Taking these results together, inhibition of NFkappaB increases apoA-I and HDL cholesterol through activation of PPARalpha in vivo and in vitro. Our data suggest a new aspect of lipid metabolism and may lead to a new paradigm for prevention and treatment of atherosclerotic disease.

DOI： 10.1074/jbc.M306336200

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Language：English   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：Japanese   Publisher：(一社)日本生理学会  

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Language：English   Publisher：UNIV CHICAGO PRESS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective We sought to establish an association between sporadic Alzheimer's disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population.
Methods A 5 kb fragment containing the putative promoter of the PSEN1 gene for randomly selected control subjects was subcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. We then constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls.
Subjects A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied.
Results We discovered a novel polymorphism with high heterozygosity on -4,752 of the PSEN1 promoter region. A significant association was observed between the -4,752 C/T polymorphism and late-onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was 1.59 (95% CI=1.01-2.51), while that of epsilon 4 vs non-epsilon 4 in APOE gene was 4.41 (95% CI=2.72-7.16). The C allele was associated with a further increase in the risk of AD in APOE epsilon 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls.
Conclusion The PSEN1 gene -4,752 C/T polymorphism modifies the risk for AD.

DOI： 10.2169/internalmedicine.41.823

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The tricarboxylate carrier protein catalyzes an electroneutral exchange across the mitochondrial inner membrane of tricarboxylate, dicarboxylate or phosphoenolpyruvate. We examined expression and localization of mitochondrial tricarboxylate carrier TCC mRNA and protein in the rat brain. TCC mRNA was ubiquitously expressed in all rat tissues examined and was abundant in brain, liver and kidney. TCC protein as well as mRNA was widely expressed in brain, and the protein expression was strong in neuronal cells in the hippocampus, the olfactory bulb, the corpus mamillare and the cerebellum. Our results suggest that this tricarboxylate carrier protein may contribute to biosynthesis and bioenergetics in neuronal cells in brain. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0169-328X(02)00139-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A missense mutation (N1411) in Presenilin-2 (PS-2) gene is associated with early-onset familial Alzheimer's disease. In this study, SK-N-SH human neuroblastoma cells were transfected with wildtype and mutant PS-2 gene to examine presenilin-2 effects on apoptosis. Serum deprivation resulted in enhanced apoptosis in mutant PS-2 comparing with wild-type PS-2. Similarly, mutant PS-2 induced lactate dehydrogenase release to greater extent than wild-type PS-2. Time course experiment demonstrated that the increase in caspase-3-like activity was more pronounced and accelerated in mutant PS-2, compared to wild-type PS-2. While a significant decrease in bcl-2, an anti-apoptotic molecule, occurred in the cells overexpressing mutant PS-2, no significant change was observed in bax, a pro-apoptotic molecule, as compared with the cells overexpressing wild-type PS-2. Our study demonstrated that mutant PS-2 induces apoptosis accompanied by increased caspase-3-like activity and decreased bcl-2 expression in neuronal cells after serum-deprivation. (C) 2002 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(02)01514-X

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE AMERICA INC  

Oxygen-regulated protein 150 kD (ORP150) is a novel endoplasmic-reticulum-associated chaperone induced by hypoxia/ischemia. Although ORP150 was sparingly upregulated in neurons from human brain undergoing ischemic stress, there was robust induction in astrocytes. Cultured neurons overexpressing ORP150 were resistant to hypoxemic stress, whereas astrocytes with inhibited ORP150 expression were more vulnerable. Mice with targeted neuronal overexpression of ORP150 had smaller strokes compared with controls. Neurons with increased ORP150 demonstrated suppressed caspase-3-like activity and enhanced brain-derived neurotrophic factor (BDNF) under hypoxia signaling. These data indicate that ORP150 is an integral participant in ischemic cytoprotective pathways.

DOI： 10.1038/85463

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Upon binding to the cAMP-response element of a gene's promoter, the transcription factor known as cAMP-response element-binding protein (CREB) facilitates transcription of many different neuronal genes including those involved with synaptic function. Based on our previous reports of gene structure (GenBank (TM) accession number AF029701), we now demonstrate that activated CREB binds to the proximal promoter of the human presenilin-1 (PS-1) gene to activate PS-l transcription in rat and in human neuronal cells. Specific stimulation of the N-methyl-D-aspartate subtype of neuronal glutamate receptors activates CREB and results in increased PS-l expression. Similarly, treatment with brain-derived neurotrophic factor activates CREB and increases PS-l expression in a dose-dependent fashion. By using adenovirus vectors expressing dominant negative forms of CREB, we were able to show that induction of PS-l expression requires the activation of CREB, Conversely, constitutive expression of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) results in activation of CREB and increased PS-1 expression that can be blocked by the addition of selective MEK inhibitors. Our findings suggest a hypothesis where stimulation of N-methyl-D-aspartate receptors signals CREB activation to enhance PS-l gene product expression that contributes to normal neuronal functions.

DOI： 10.1074/jbc.M006153200

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Inheritance of the ε-4 allele of the apolipoprotein E gene (APOE4) is a major risk factor for the development of Alzheimer's disease (AD). Although the association between APOE4 and AD is well documented, the mechanism by which apolipoprotein E exerts an isoform-specific effect on neurons in disease is unknown. In this report, we demonstrate that apoE4 stimulates the transcriptional activity of cAMP-response element-binding protein (CREB) by activating the extracellular signal-regulated kinase (ERK) cascade in rat primary hippocampal neurons. In contrast, apoE3 was unable to stimulate CREB transcriptional activity and unable to activate the ERK pathway. Elevation of intracellular Ca2+ levels are also involved because treatment with receptor-associated protein, nifedipine, MK801, removal of Ca2+ from the medium and dantrolene all served to inhibit calcium elevation and attenuate the activation of CREB. Treatment with an apoE peptide was also found to facilitate transcription of the CREB-dependent genes, c-fos and Bcl-2. In contrast to treatment with apoE3, our findings suggest apoE4 and apoE-peptide induce a novel signaling pathway.

DOI： 10.1074/jbc.M005070200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Survival factors suppress apoptosis by activating the serine/threonine kinase Akt. To investigate the molecular mechanism underlying activated Akt's ability to protect neurons from hypoxia or nitric oxide (NO) toxicity, we focused on the apoptosis-related functions of p53 and caspases, We eliminated p53 by employing p53-deficient neurons and increased p53 by infection with recombinant adenovirus capable of transducing p53 expression, and we now show that p53 is implicated in the apoptosis induced by hypoxia or NO treatments of primary cultured hippocampal neurons. Although hypoxia and NO induced p53, treatment with insulin-like growth factor-1 significantly inhibited caspase-3-like activation, neuronal death and transcriptional activity of p53. These insulin-like growth factor-1 effects are prevented by wortmannin, a phosphatidylinositol 3-kinase inhibitor, Adenovirus-mediated expression of activated-Akt kinase suppressed p53-dependent transcriptional activation of responsive genes such as Bax, suppressed caspase-3-like protease activity and suppressed neuronal cell death with no effect on the cellular accumulation and nuclear translocation of p53. In contrast, overexpression of kinase-defective Akt failed to suppress these same activities. These results suggest a mechanism where Akt kinase activation reduces p53's transcriptional activity that ultimately rescues neurons from hypoxia- or NO-mediated cell death.

DOI： 10.1074/jbc.M008552200

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Language：Japanese   Publisher：金原出版(株)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Low density lipoprotein (LDL) receptor-related protein (LRP) gene polymorphisms located in the 5' region and in exon 3, and the apolipoprotein E (APOE) genotype were determined in 100 Japanese patients affected by late-onset Alzheimer's disease (AD). We matched 246 controls for age and found no association between the polymorphism located in the 5' region of the LRP gene. The distribution of LRP exon 3 genotypes and alleles did not differ between AD and the control groups. However, the frequency of T allele in the Alzheimer's group having APOE-epsilon 4 was lower than that in the control group having APOE-epsilon 4, but it was only marginally significant (p = 0.022). Age of onset was significantly younger in the patients with CC genotype than those carrying the T allele (p = 0.03), and this trend was more evident among non-APOE-epsilon 4 carriers (p = 0.008). These results support the possibility that ApoE and LRP may contribute to the development of AD.

DOI： 10.1034/j.1399-0004.2000.580410.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

As a model of the reperfusion injury found in stroke, we have exposed neurons to hypoxia followed by reoxygenation. Neurons treated with hypoxia/reoxygenation (H/R) respond by activating nuclear factor-kappa B (NF kappa B), releasing cytochrome c from their mitochondria, and ultimately dying. Further supporting an apoptotic mechanism, expression of the antiapoptotic Bcl-2 and Bcl-x proteins was increased following H/R. In this model, adenoviral-mediated transduction of I kappa B expression inhibited NF kappa B activation and significantly accelerated cytochrome c release and caspase-dependent neuronal death. At the same time, expression of mutated I kappa B prevented the increased expression of endogenous Bcl-2 and Bcl-x. In the presence of mutated I kappa B, singular overexpression of only Bcl-2 by adenoviral-mediated transduction significantly inhibited cytochrome c release, caspase-3-like activation, and cell death in response to H/R. These findings suggest a pathway where NF kappa B activation induces overexpression of Bcl-2 and Bcl-x, which function to prevent apoptotic cell death following H/R treatments.

DOI： 10.1046/j.1471-4159.2000.0750683.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Emerging data indicate that growth factors such as insulin-like growth factor-1 (IGF-1) prevent neuronal death due to nitric oxide (NO) toxicity. On the other hand, growth factors can promote cell survival by acting on phosphatidylinositol 3-kinase (PI3-kinase) and its downstream target, serine-threonine kinase Akt, in various types of cells. Here, we examined the mechanism by which IGF-1 inhibits neuronal apoptosis induced by NO in primary hippocampal neurons. IGF-1 was capable of preventing apoptosis and caspase-3-like activation induced by a NO donor, sodium nitroprusside or 3-morpholin-osydnonimine. Incubation of neurons with a PI3-kinase inhibitor, wortmannin or LY294002, blocked the effects of IGF-1 on NO-induced neurotoxicity and caspase-3-like activation. In addition, the PI3-kinase inhibitors blocked the effect of IGF-1 on down-regulation in Bcl-2 and upregulation in Bax expression induced by NO. Adenovirus-mediated overexpression of the activated form of Akt significantly inhibited NO-induced cell death, caspase-3-like activation, and changes in Bcl-2 and Bax expression. Moreover, expression of the kinase-defective form of Akt almost completely blocked the effects of IGF-1. These findings suggest that activation of Akt is necessary and sufficient for the effect of IGF-1 and is capable of preventing NO-induced apoptosis by modulating the NO-induced changes in Bcl-2 and Bax expression.

DOI： 10.1046/j.1471-4159.1999.02037.x

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Werner syndrome (WS) is an autosomal recessive genetic disease characterized by many age-related features. The gene responsible for WS (WRN) has been isolated and contains a helicase domain, but its function is unknown. Six different mutations throughout the WRN gene have been reported in the Japanese population. We have studied whether patients with a specific mutation exhibit distinct phenotypes from others. Fourteen patients with different mutations showed almost the same signs and symptoms and, therefore, the C terminal part of the product appears to be crucial for its function, although other parts may be important as well. Haplotype analyses using 13 microsatellites covering the 2.8-3.0 cM WRN region showed that two out of six different mutations had founder chromosomes. These two founder chromosomes may be evenly distributed throughout the western part of Japan, suggesting that these mutations go back to a lime earlier than 1400 years ago. (C) 1997 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0047-6374(97)00112-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The presenilin-1 (PS-1) gene encodes at least three separate mRNA transcripts from its 12 exons, which are spread over 50 kilobase pairs of mouse DNA. The first transcript begins with exon 1A, whereas the other transcripts begin with exon 1B. Different portions of exon 1B are spliced to give long and short mRNAs. The expression of all of these transcripts depends on a single promoter located just upstream of exon 1A. Although this region lacks a TATA box and a number of common initiator sequences, it does contain a CAAT box, a heat-shock responsive element, a polyomavirus enhancer activator-3 site, an Ets 1-3 site, and multiple-Sp1 and multiple-Ap2 binding sites, which are typically found in eukaryotic promoters. We have combined a reporter gene with various portions of this putative PS-1 promoter and measured firefly luciferase activity relative to an internal renilla luciferase standard. We identified a 25-base pair fragment spanning the 5'-transcription start site of exon 1A as containing the core of the promoter activity. The sequences downstream of this region had undetectable promoter activity, suggesting that this core element is the gene's only promoter, and it controls expression of all three transcripts. Although human PS-1 mRNA expression is clearly different from the mouse PS-1 mRNA pattern, the human and mouse core promoters do share limited homology.

DOI： 10.1074/jbc.272.38.23489

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Language：English   Publisher：INT SOC NEUROPATHOLOGY  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

We have constructed a yeast artificial chromosome (YAC) and P1 contig in the 8p12-p21 region. The contig comprises 16 overlapping YAC clones and 44 overlapping P1 clones. Twelve dinucleotide-repeat polymorphic sequence-tagged site (STS) markers that were previously isolated mainly from these YAC and P1 clones were genetically mapped. A total of 46 nonpolymorphic STS markers were newly established mainly from the YAC and P1 clone end fragments, and 28 of the 46 nonpolymorphic STSs, as well as the 12 polymorphic STSs, were also mapped physically onto the contig based on STS content analysis of YAC pools and of the P1 and YAC clones. As a result, the YAC and P1 clones were assembled into a single contig covering a minimum of 1.5 Mb physically and 2.8 cM genetically with 12 polymorphic and 28 nonpolymorphic STSs within the 8p12-p21 region. Average STS spacing in the contig was estimated to be 40 kb/STS. In addition, further characterization of the contig suggested that this contig includes a region where genetic recombination occurs frequently. Thus, the resulting cloned region, together with densely mapped STS markers on the contig, should help to promote our understanding of this region. (C) 1997 Academic Press.

DOI： 10.1006/geno.1997.4619

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Werner syndrome (WS) is an autosomal recessive dosorder characterized by the premature ocurrence of many age-related features. To identify the gene for WS (WRN), previously assigned to the 8p 12-21 region, we used the positional cloning strategy. First, we constructed a genetic map. The map comprises 34 dinucleotide repeat polymorphic markers and spans about 43 cM across the 8pl2-21 region. Second, we analyzed 58 patiens for the 34 markers by homozygosity analysis to refine the WRN locus, resulting in narrowing the position of the WRN locus to 1.6 cM. Third, we tested linkage disequilibrium between the WRN locus and 16 dinucleotide repeat polymorphic marker loci positioned within the WRN candidate region. This resulted in detection of linkage disequilibrium between WRN and D8S1223 (p&lt
0.05). D8S1055 (p&lt
O.OI). D8S1445 (p&lt
0.001). D8S339 (p&lt
0.001), GSR1 (p&lt
0.001), GSR2 (p&lt
0.001), and D8S1444 (p&lt
0.05). Fourth, to construct a physical map containing all of these 7 markers, we assembled 16 YAC clones and 44 PI clones into a single contig covering a minimum of 1.5 Mb physically and 2.8 cM genetically with 12 polymorphic and 28 nonpolymorphic STSs within the 8pl2-21 region. These YAC and PI clones were used to isolated several candidate genes. Fifth, we also construct a EST map on this cloned region and integrated the EST map into a genetic and physical map. This resulting map should help to promote our understanding of this region.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

Werner syndrome (WS) is an autosomal recessive disorder characterized by the premature occurrence of many age-related features. Previously, the WS gene (WRN) was mapped between D8S131 and D8S87, in an 8.3-cM interval. In this study, regions of homozygosity in 36 WS patients from inbred families were searched for by genotyping for 35 dinucleotide repeat polymorphic markers to narrow down the WRN critical region. The region most consistently homozygous in these patients was between the D8S1219/D8S1220 cluster and D8S278, within a 4.4-cM interval. For 16 markers mapped in this interval, 24 WS patients (22 Japanese patients and 2 Caucasian patients) in whom consanguinity failed to be proved were also genotyped, under the assumption that some of these patients might still be from consanguineous marriages. The data were analyzed by Fisher's exact test with a 2 x 2 contingency table for the 22 Japanese patients, excluding the 2 Caucasian patients. The frequencies of homozygosity in the 22 patients at 10 of 16 markers tested were significantly higher than those detected in the general population. Analysis of homozygosity patterns indicated that the region most consistently homozygous was between D8S1445 and D8S278. Thus the WRN locus is most likely between the two markers D8S1445 and D8S278, in a 1.6-cM interval. (C) 1996 Academic Press, Inc.

DOI： 10.1006/geno.1996.0433

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

A polymorphic dinucleotide (CA) repeat clone was isolated from a CEPH mega-YAC clone (936F7), and was localized to chromosome 8 using a panel of 13 mouse/human somatic cell hybrids.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

Two polymorphic dinucleotide (CA) repeat clones were isolated from a CEPH mega-YAC clone (844E2), and were localized to chromosome 8 using a panel of 13 mouse/human somatic cell hybrids.

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Language：English   Publisher：LANCET LTD  

DOI： 10.1016/S0140-6736(96)90261-5

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Werner syndrome (WRN) is an autosomal recessive disorder characterized by premature aging which has been mapped to the short arm of chromosome 8, 8p11.2-pl2. In order to refine the genetic map around the WRN region, we have isolated eight microsatellites for this region from a microdissection library. We typed members of Japanese families with WRN on the basis of homozygosity mapping analysis. There was no obligate recombination between the WRN locus and microsatellite clone, MS8-134 (D8S1055). The maximum lod score was 20.28 at theta=0.00. Alleles for MS8-134 showed association with WRN in a case-control study (OR=3.55, 95% CI 1.56-8.07, P&lt
0.01). Such microsatellites from a microdissection library of the definite chromosome region may be useful for positional cloning of the WRN gene.

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Werner syndrome (WRN) is an autosomal recessive disorder characterized by premature aging which has been mapped to the short arm of chromosome 8, 8p11.2-p12. In order to refine the genetic map around the WRN region, we have isolated eight microsatellites for this region from a microdissection library. We typed members of Japanese families with WRN on the basis of homozygosity mapping analysis. There was no obligate recombination between the WRN locus and microsatellite clone, MS8-134 (D8S1055). The maximum lod score was 20.28 at theta=0.00. Alleles for MS8-134 showed association with WRN in a case-control study (OR=3.55, 95% CI 1.56-8.07, P&lt
0.01). Such microsatellites from a microdissection library of the definite chromosome region may be useful for positional cloning of the WRN gene.

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Language：English   Publisher：UNIV CHICAGO PRESS  

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Three polymorphic dinucleotide (CA) repeat clones were isolated from a CEPH mega-YAC clone (936F7), and were localized to chromosome 8 using a panel of 13 mouse/human somatic cell hybrids. © 1995 The Japan Society of Human Genetics.

DOI： 10.1007/BF01876189

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Language：English   Publisher：TOKYO MEDICAL DENTAL UNIV  

A highly polymorphic dinucleotide (CA) repeat clone was isolated from a CEPH mega-YAC clone (844E2), and was localized to chromosome 8 using a panel of 13 mouse/human somatic cell hybrids.

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Language：English   Publisher：JAPAN SOC INTERNAL MEDICINE  

A 40-year-old female patient with Werner's syndrome (WS) suffering from thyroid cancer and myelodysplastic syndrome (MDS) is reported, She had been diagnosed as having WS complicated with thyroid cancer seven years previously, Total thyroidectomy and radioactive iodine (I-131, 100 mCi/year) therapy for seven years had slowed the progression of thyroid cancer. She suffered a sudden onset of MDS at the age of 40 years. After six months she died from overt leukemia, We found an additional chromosome aberration of chromosome 10 in the progression of leukemia from MDS.

DOI： 10.2169/internalmedicine.34.863

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Werner syndrome (WRN) is an autosomal recessive disorder characterized by premature aging that has been mapped to the short arm of chromosome 8, 8p11.2-p12. To refine the genetic map around the WRN region, we have isolated eight microsatellites for this region from a microdissection library. We typed members of Japanese families with WRN on the basis of homozygosity mapping analysis. There was no obligate recombination between the WRN locus and microsatellite clone, MS8-134 (D8S1055). The maximum lod score was 20.28 at theta = 0.00. Alleles for MS8-134 showed association with WRN in a case-control study (OR = 3.55, 95% CI 1.56-8.07, P &lt; 0.01). Such microsatellites hom a microdissection Library of the definite chromosome region may be useful for positional cloning of the WRN gene. (C) 1995 Academic Press, Inc.

DOI： 10.1006/geno.1995.1189

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

A polymorphic CA repeat was isolated from a chromosome microdissection library and was mapped to chromosome 8q11.23-q21.3 using human-mouse cell hybrids and linkage analysis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：日本老年医学会  

Werner syndrome (WRN) is a rare autosomal recessive disorder, one of the progeroid syndromes, and is characterized by features of premature aging. The incidence of WRN in the Japanese population, 1 in 200,000, is higher than than that in the Caucasian population. The genetic defect of WRN is unknown. But genetic linkage to several markers on the short arm of chromosome 8 has been reported recently. Here, we studied one family with WRN in which an affected individual had a papillary thyroid carcinoma and myelodysplastic syndrome. Using 4 microsatellites closely located to the WRN locus: D8S360, D8S1055, D8S339 and ANK1, we analyzed the genotypes of this patient, her three siblings and her parents, who were first cousins. The mutative haplotype, identified through the generations in pedigree, helps detect a carrier or a presymptomatic patient. The eldest sister inherited two normal haplotypes, but the second sister inherited one mutative haplotype. There was no difference in clinical signs and symptoms between these sisters. when the WRN gene is isolated, it will help us understand the mechanism of aging. © 1995, The Japan Geriatrics Society. All rights reserved.

DOI： 10.3143/geriatrics.32.817

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

A polymorphic dinucleotide (CA) repeat clone isolated from a chromosome microdissection library was mapped to chromosome 8p22-p23.1 using human-mouse cell hybrids and linkage analysis of 5 CEPH families.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

Werner's syndrome (WS) is a rare autosomal recessive disorder, one of the progeroid syndromes, characterized by features of premature aging. The genetic defect in WS is unknown but recently the genetic linkage of WS to several markers on the short arm of chromosome 8 has been reported. Genetic analysis of 25 families with WS demonstrated that D8S339 was the closest marker linked to the gene locus for Werner's syndrome (WRN), with a peak lod score of 18.29 at recombination frequency 0.001, and showed a linkage disequilibrium with the WRN locus. We studied two unrelated families with WS using ANK1, D8S339, and D8S360. The mutative haplotype identified through the generations in pedigrees provides a means of carrier detection and presymptomatic diagnosis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

A polymorphic dinucleotide (CA) repeat clone isolated from a chromosome microdissection library was mapped to chromosome 8p11.2-p12 using human-mouse cell hybrids and linkage analysis of 5 CEPH families.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

Six polymorphic dinucleotide (CA) repeat clones isolated from a chromosome microdissection library were mapped to chromosome 7 using human-mouse cell hybrids and linkage analysis of 5 CEPH families.

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Language：Japanese   Publisher：(株)日本臨床社  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS UNITED KINGDOM  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOKYO MEDICAL DENTAL UNIV  

We have constructed a new genetic linkage map of the Werner syndrome (WRN) region, using microsatellites from a library which was developed by a chromosome microdissection and enzymatic amplification method. These microsatellites were used to genotype members of CEPH families using a simplified detection system of polymerase chain reaction (PCR) products. Two-point analysis was used to assign 4 microsatellite markers relative to each marker and other markers reported in the CEPH public data base. We confirmed that these 4 markers are located to the WRN region, 8p11.2-p22. Such microsatellites microdissected from the definite chromosome region may be useful for positional cloning.

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：The Japan Geriatrics Society  

DOI： 10.3143/geriatrics.43.610

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER SCIENCE INC  

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Language：Japanese   Publisher：社団法人 日本解剖学会  

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Language：Japanese   Publisher：一般社団法人 日本老年医学会  

転写因子cAMP-response element binding protein (CREB) はシナプスの可塑性に関係した多数の遺伝子の発現を調節している. 我々はCREBがアルツハイマー病原因遺伝子の一つプレセニリン-1 (PS-1) のプロモーター領域に結合し, その発現を誘導することを証明した. このことはPS-1自体がシナプス機能に関係している可能性を示唆する. また, このようなPS-1の発現調節機構の解明は家族性アルツハイマー病の発症予防に結びつく可能性を秘めると考えられる.

DOI： 10.3143/geriatrics.38.772

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