Updated on 2022/05/25

写真a

 
SAWAMURA, Naoya
 
Affiliation
Research Council (Research Organization), Research Organization for Nano & Life Innovation
Job title
Senior Researcher(Professor)

Concurrent Post

  • Faculty of International Research and Education   School of International Liberal Studies

  • Faculty of Science and Engineering   School of Advanced Science and Engineering

Education

  •  
    -
    2000

    University of Tokyo   Graduate School, Division of Medical Sciences  

  •  
    -
    1996

    University of Tsukuba   Graduate School, Division of Medical Science  

  •  
    -
    1994

    Tokyo University of Science   Faculty of Science and Engineering  

Degree

  • 東京大学   博士(医学)

Research Experience

  • 2013.04
    -
     

    Waseda University   Faculty of Science and Engineering

  • 2009.04
    -
     

    Waseda University   Faculty of Science and Engineering

  • 2008.10
    -
     

    Waseda University   Consolidated Research Institute for Advanced Science and Medical Care

  • 2006.07
    -
     

    Waseda University   Consolidated Research Institute for Advanced Science and Medical Care

  • 2003.03
    -
    2005.03

    日本学術振興会 海外特別研究員

  • 2003.03
    -
     

    ジョンズホプキンス大学医学部 精神医学部門、Postdoctoral Fellow

  • 2002.04
    -
    2003.02

    日本学術振興会 科学技術特別研究員

  • 2001.01
    -
    2002.03

    科学技術振興事業団 科学技術特別研究員

  • 2000.04
    -
    2000.12

    長寿科学振興財団 リサーチレジデント

  • 2000.04
    -
     

    国立長寿医療研究センター 痴呆疾患研究部 臨床研究室

▼display all

Professional Memberships

  •  
     
     

    The Japanece Society for Neurochemistry

  •  
     
     

    日本進化学会

 

Research Areas

  • Neuroscience-general

Research Interests

  • 神経化学、神経変性疾患、統合失調症、精神疾患、アルツハイマー病、発達障害、ミトコンドリア、分子進化

Papers

  • Proliferation and differentiation of primary bovine myoblasts using Chlorella vulgaris extract for sustainable production of cultured meat.

    Yuta Okamoto, Yuji Haraguchi, Azumi Yoshida, Hironobu Takahashi, Kumiko Yamanaka, Naoya Sawamura, Toru Asahi, Tatsuya Shimizu

    Biotechnology progress     e3239  2022.01  [International journal]

     View Summary

    Recently, cultured meat obtained from livestock-derived cells is being considered as a sustainable food source that reduces the use of natural resources. This study aimed to show that nutrients extracted from Chlorella vulgaris were beneficial in the culture of primary bovine myoblasts (PBMs), a major cell source for cultured meat production. Nutrients (glucose, amino acids, and vitamins) present in the animal-cell culture media were effectively recovered from C. vulgaris using acid hydrolysis treatment. On culture in nutrient-free inorganic salt solution, cell death was induced in most PBMs after 6 days of cultivation. However, the addition of C. vulgaris extract (CVE) significantly improved PBM viability, which was comparable to the viability in conventional culture medium (Dulbecco's modified Eagle's medium). Furthermore, by adding horse serum to induce differentiation, the formation of myotubes was confirmed when CVE were used. Together, the results showed that CVE could be used as an alternative to the conventional culture medium for PBMs. These findings will not only lower the environmental risks associated with the establishment of this eco-friendly cell culture system, but also highlight microalgae as a potent nutrient source that can replace conventional grain-dependent nutrient sources.

    DOI PubMed

  • Rapid evolution of mammalian APLP1 as a synaptic adhesion molecule.

    Wataru Onodera, Toru Asahi, Naoya Sawamura

    Scientific reports   11 ( 1 ) 11305 - 11305  2021.05  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Amyloid precursor protein (APP) family members are involved in essential neuronal development including neurite outgrowth, neuronal migration and maturation of synapse and neuromuscular junction. Among the APP gene family members, amyloid precursor-like protein 1 (APLP1) is selectively expressed in neurons and has specialized functions during synaptogenesis. Although a potential role for APLP1 in neuronal evolution has been indicated, its precise evolutionary and functional contributions are unknown. This study shows the molecular evolution of the vertebrate APP family based on phylogenetic analysis, while contrasting the evolutionary differences within the APP family. Phylogenetic analysis showed 15 times higher substitution rate that is driven by positive selection at the stem branch of the mammalian APLP1, resulting in dissimilar protein sequences compared to APP/APLP2. Docking simulation identified one positively selected site in APLP1 that alters the heparin-binding site, which could affect its function, and dimerization rate. Furthermore, the evolutionary rate covariation between the mammalian APP family and synaptic adhesion molecules (SAMs) was confirmed, indicating that only APLP1 has evolved to gain synaptic adhesion property. Overall, our results suggest that the enhanced synaptogenesis property of APLP1 as one of the SAMs may have played a role in mammalian brain evolution.

    DOI PubMed

  • Cereblon-mediated degradation of the amyloid precursor protein via the ubiquitin-proteasome pathway.

    Tomotaka Kurihara, Toru Asahi, Naoya Sawamura

    Biochemical and biophysical research communications    2020.01  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Cereblon (CRBN) was identified as a gene that causes intellectual disabilities. The encoded CRBN protein, containing 442 amino acids, is located in several organs. Cytosolic CRBN was reported to mainly act as a component of the E3 ubiquitin ligase complex. CRBN is one of the substrate receptors of the E3 ubiquitin ligase complex and promotes the degradation of targeted proteins. Studies have reported that CRBN recognizes the C-terminal region of the amyloid precursor protein (APP), a protein known for its involvement in the development of Alzheimer's disease. Although CRBN may interact with the C-terminal region of APP in mice, the CRBN-mediated degradation mechanism of human APP remains unclear. Here, we analyzed the CRBN-mediated degradation mechanism of human APP via the ubiquitin-proteasome system. Immunoprecipitation experiments showed that CRBN interacts with human full-length APP via its C-terminal region. Next, we examined CRBN-mediated degradation of APP in the ubiquitin-proteasome system. CRBN recognizes Lys751 in human APP and ubiquitinates it in SH-SY5Y cells. Overexpression of CRBN decreased wild-type APP expression levels. In contrast, the expression level of K751R APP remained unchanged by CRBN overexpression, while knockdown of endogenous CRBN increased APP levels. As such, our results suggest that CRBN ubiquitinates Lys751 of human APP thereby degrading it via the ubiquitin-proteasome system.

    DOI PubMed

  • Light-driven activation of mitochondrial proton-motive force improves motor behaviors in a Drosophila model of Parkinson's disease.

    Imai Y, Inoshita T, Meng H, Shiba-Fukushima K, Hara KY, Sawamura N, Hattori N

    Communications biology   2   424  2019.12  [Refereed]

    DOI PubMed

  • Mammalian cell cultivation using nutrients extracted from microalgae.

    Okamoto Y, Haraguchi Y, Sawamura N, Asahi T, Shimizu T

    Biotechnology progress   36 ( 2 ) e2941  2019.11  [Refereed]

    DOI PubMed

  • Data for positive selection test and co-evolutionary analysis on mammalian cereblon

    Wataru Onodera, Toru Asahi, Naoya Sawamura

    Data in Brief   26  2019.10  [Refereed]

    Authorship:Corresponding author

     View Summary

    © 2019 The Author(s) Cereblon (CRBN) is a substrate recognition subunit of the CRL4 E3 ubiquitin ligase complex, directly binding to specific substrates for poly-ubiquitination followed by proteasome-dependent degradation of proteins. Cellular CRBN is responsible for energy metabolism, ion-channel activation, and cellular stress response through binding to proteins related to the respective pathways. As CRBN binds to various proteins, the selective pressure at the interacting surface is expected to result in functional divergence. Here, we present two mammalian CRBN datasets of molecular evolutionary analyses. (1) The multiple sequence alignment data shows that positive selection occurred, determined with a dN/dS calculation. (2) Data on co-evolutionary analysis between vertebrate CRBN and related proteins are represented by calculating the correlation coefficient based on the comparison of phylogenetic trees. Co-evolutionary analysis shows the similarity of evolutionary traits of two proteins. Further molecular, functional interpretation of these analyses is explained in ‘Positive selection of Cereblon modified function including its E3 Ubiquitin Ligase activity and binding efficiency with AMPK’ (W. Onodera, T. Asahi, N. Sawamura, Positive selection of cereblon modified function including its E3 ubiquitin ligase activity and binding efficiency with AMPK. Mol Phylogenet Evol. (2019) 135:78-85. [1]).

    DOI

  • Neuroprotective effects of thalidomide on cerebral infarction via AMPK pathway

    澤村 直哉, 朝日 透, 高木 教夫

    医学のあゆみ   269 ( 12 ) 915 - 919  2019.06

    CiNii

  • Positive Selection of Cereblon Modified Function Including its E3 Ubiquitin Ligase Activity and Binding Efficiency with AMPK.

    Onodera W, Asahi T, Sawamura N

    Molecular phylogenetics and evolution    2019.03  [Refereed]

    Authorship:Corresponding author

    DOI PubMed

  • The Neuroprotective Effect of Thalidomide against Ischemia through the Cereblon-mediated Repression of AMPK Activity

    Naoya Sawamura, Mariko Yamada, Miku Fujiwara, Haruka Yamada, Hideki Hayashi, Norio Takagi, Toru Asahi

    Scientific Reports   8 ( 1 )  2018.12

     View Summary

    Thalidomide was originally used as a sedative and found to be a teratogen, but now thalidomide and its derivatives are widely used to treat haematologic malignancies. Accumulated evidence suggests that thalidomide suppresses nerve cell death in neurologic model mice. However, detailed molecular mechanisms are unknown. Here we examined the molecular mechanism of thalidomide's neuroprotective effects, focusing on its target protein, cereblon (CRBN), and its binding protein, AMP-activated protein kinase (AMPK), which plays an important role in maintaining intracellular energy homeostasis in the brain. We used a cerebral ischemia rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). Thalidomide treatment significantly decreased the infarct volume and neurological deficits of MCAO/R rats. AMPK was the key signalling protein in this mechanism. Furthermore, we considered that the AMPK-CRBN interaction was altered when neuroprotective action by thalidomide occurred in cells under ischemic conditions. Binding was strong between AMPK and CRBN in normal SH-SY5Y cells, but was weakened by the addition of H2O2. However, when thalidomide was administered at the same time as H2O2, the binding of AMPK and CRBN was partly restored. These results suggest that thalidomide inhibits the activity of AMPK via CRBN under oxidative stress and suppresses nerve cell death.

    DOI PubMed

  • Cholinergic receptor, nicotinic, alpha 7 as a target molecule of Arctic mutant amyloid β.

    Sawamura N, Ju Y, Asahi T

    Neural regeneration research   13 ( 8 ) 1360 - 1361  2018.08  [Refereed]

    DOI PubMed

  • Antioxidant activity of Ge-132, a synthetic organic germanium, on cultured mammalian cells

    Takeyoshi Wada, Takashi Hanyu, Kota Nozaki, Kosuke Kataoka, Tomoro Kawatani, Toru Asahi, Naoya Sawamura

    Biological and Pharmaceutical Bulletin   41 ( 5 ) 749 - 753  2018  [Refereed]

     View Summary

    Ge-132 is a synthetic organic germanium that is used as a dietary supplement. The antioxidant activity of Ge-132 on cultured mammalian cells was investigated in this study. First, Ge-132 cytotoxicity on mammalian cultured cells was determined by measuring lactate dehydrogenase (LDH) levels. Ge-132 had no cytotoxic effect on three different cell lines. Second, the cell proliferative effect of Ge-132 was determined by measuring ATP content of whole cells and counting them. Ge-132 treatment of Chinese hamster ovary (CHO-K1) and SH-SY5Y cells promoted cell proliferation in a dose-dependent manner. Finally, antioxidant activity of Ge-132 against hydrogen peroxide-induced oxidative stress was determined by measuring the levels of intracellular reactive oxygen species (ROS) and carbonylated proteins. Pre-incubation of CHO-K1 and SH-SY5Y cells with Ge-132 suppressed intracellular ROS production and carbonylated protein levels induced by hydrogen peroxide. Our results suggest that Ge-132 has antioxidant activity against hydrogen peroxide-induced oxidative stress.

    DOI PubMed

  • Arctic A beta 40 blocks the nicotine-induced neuroprotective effect of CHRNA7 by inhibiting the ERK1/2 pathway in human neuroblastoma cells

    Ye Ju, Toru Asahi, Naoya Sawamura

    NEUROCHEMISTRY INTERNATIONAL   110   49 - 56  2017.11  [Refereed]

     View Summary

    Amyloid 13 protein (A beta) plays a central role in Alzheimer's disease (AD) pathogenesis. Point mutations in the A beta sequence, which cluster around the central hydrophobic core of the peptide, are associated with familial AD (FAD). Several mutations have been identified, with the Arctic mutation exhibiting a purely cognitive phenotype that is typical of AD. Our previous findings suggest that Arctic A beta 40 binds to and aggregates with CHRNA7, thereby inhibiting the calcium response and signaling pathways downstream of the receptor. Activation of CHRNA7 is neuroprotective both in vitro and in vivo. Therefore, in the present study, we investigated whether Arctic A beta 40 affects neuronal survival and/or death via CHRNA7. Using human neuroblastoma SH-SY5Y cells, we found that the neuroprotective function of CHRNA7 is blocked by CHRNA7 knockdown using RNA interference. Furthermore, Arctic A beta 40 blocked the neuroprotective effect of nicotine by inhibiting the ERK1/2 pathway downstream of CHRNA7. Moreover, we show that ERK1/2 activation mediates the neuroprotective effect of nicotine against oxidative stress. Collectively, our findings further our understanding of the molecular pathogenesis of Arctic FAD. (C) 2017 Elsevier Ltd. All rights reserved.

    DOI

  • Arctic Aβ40 blocks the nicotine-induced neuroprotective effect of CHRNA7 by inhibiting the ERK1/2 pathway in human neuroblastoma cells

    Ye Ju, Toru Asahi, Naoya Sawamura

    Neurochemistry International   110   49 - 56  2017.11

     View Summary

    Amyloid β protein (Aβ) plays a central role in Alzheimer's disease (AD) pathogenesis. Point mutations in the Aβ sequence, which cluster around the central hydrophobic core of the peptide, are associated with familial AD (FAD). Several mutations have been identified, with the Arctic mutation exhibiting a purely cognitive phenotype that is typical of AD. Our previous findings suggest that Arctic Aβ40 binds to and aggregates with CHRNA7, thereby inhibiting the calcium response and signaling pathways downstream of the receptor. Activation of CHRNA7 is neuroprotective both in vitro and in vivo. Therefore, in the present study, we investigated whether Arctic Aβ40 affects neuronal survival and/or death via CHRNA7. Using human neuroblastoma SH-SY5Y cells, we found that the neuroprotective function of CHRNA7 is blocked by CHRNA7 knockdown using RNA interference. Furthermore, Arctic Aβ40 blocked the neuroprotective effect of nicotine by inhibiting the ERK1/2 pathway downstream of CHRNA7. Moreover, we show that ERK1/2 activation mediates the neuroprotective effect of nicotine against oxidative stress. Collectively, our findings further our understanding of the molecular pathogenesis of Arctic FAD.

    DOI PubMed

  • Ohgata, the Single Drosophila Ortholog of Human Cereblon, Regulates Insulin Signaling-dependent Organismic Growth

    Satoru Wakabayashi, Naoya Sawamura, Andre Voelzmann, Meike Broemer, Toru Asahi, Michael Hoch

    JOURNAL OF BIOLOGICAL CHEMISTRY   291 ( 48 ) 25120 - 25132  2016.11  [Refereed]

     View Summary

    Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning, and memory formation, and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo, however, are still scarce. Here we identify Ohgata (OHGT), the Drosophila ortholog of CRBN, as a regulator of insulin signaling-mediated growth. Using ohgt mutants that we generated by targeted mutagenesis, we show that its loss results in increased body weight and organ size without changes of the body proportions. We demonstrate that ohgt knockdown in the fat body, an organ analogous to mammalian liver and adipose tissue, phenocopies the growth phenotypes. We further show that overgrowth is due to an elevation of insulin signaling in ohgt mutants and to the down-regulation of inhibitory cofactors of circulating Drosophila insulin-like peptides (DILPs), named acid-labile subunit and imaginal morphogenesis protein-late 2. The two inhibitory proteins were previously shown to be components of a heterotrimeric complex with growth-promoting DILP2 and DILP5. Our study reveals OHGT as a novel regulator of insulin-dependent organismic growth in Drosophila.

    DOI PubMed

  • Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    Takeyoshi Wada, Toru Asahi, Naoya Sawamura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   477 ( 3 ) 388 - 394  2016.08

     View Summary

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. (C) 2016 Elsevier Inc. All rights reserved.

    DOI PubMed

  • Mitochondrial cereblon functions as a Lon-type protease

    Kosuke Kataoka, China Nakamura, Toru Asahi, Naoya Sawamura

    SCIENTIFIC REPORTS   6   29986  2016.07  [Refereed]

     View Summary

    Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix, and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. However, whether CRBN has Lon protease-like function remains unknown. Here, we determined if CRBN has a protective function against oxidative stress, similar to Lon protease. We report that CRBN partially distributes in mitochondria, suggesting it has a mitochondrial function. To specify the mitochondrial role of CRBN, we mitochondrially expressed CRBN in human neuroblastoma SH-SY5Y cells. The resulting stable SH-SY5Y cell line showed no apparent effect on the mitochondrial functions of fusion, fission, and membrane potential. However, mitochondrially expressed CRBN exhibited protease activity, and was induced by oxidative stress. In addition, stably expressed cells exhibited suppressed neuronal cell death induced by hydrogen peroxide. These results suggest that CRBN functions specifically as a Lon-type protease in mitochondria.

    DOI PubMed

  • Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction

    Naoya Sawamura, Satoru Wakabayashi, Kodai Matsumoto, Haruka Yamada, Toru Asahi

    Biochemical and Biophysical Research Communications   464 ( 4 ) 1054 - 1059  2015.09

     View Summary

    Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition.

    DOI PubMed

  • Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction

    Naoya Sawamura, Satoru Wakabayashi, Kodai Matsumoto, Haruka Yamada, Toru Asahi

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   464 ( 4 ) 1054 - 1059  2015.09  [Refereed]

     View Summary

    Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition. (C) 2015 Elsevier Inc. All rights reserved.

    DOI

  • Arctic mutant A beta 40 aggregates on alpha 7 nicotinic acetylcholine receptors and inhibits their functions

    Ye Ju, Toru Asahi, Naoya Sawamura

    JOURNAL OF NEUROCHEMISTRY   131 ( 5 ) 667 - 674  2014.12

     View Summary

    Amyloid protein (A beta) plays a central role in the pathogenesis of Alzheimer's disease (AD). Point mutations within the A sequence associated with familial AD (FAD) are clustered around the central hydrophobic core of A. Several types of mutations within the A sequence have been identified, and the Arctic' mutation (E22G) has a purely cognitive phenotype typical of AD. Previous studies have shown that the primary result of the Arctic' mutation is increased formation of A protofibrils. However, the molecular mechanism underlying this effect remains unknown. A42 binds to a neuronal nicotinic acetylcholine receptor subunit, neuronal acetylcholine receptor subunit alpha-7 (CHRNA7), with high affinity and, thus, may be involved in the pathogenesis of AD. Therefore, to clarify the molecular mechanism of Arctic mutation-mediated FAD, we focused on CHRNA7 as a target molecule of Arctic A. We performed an in vitro binding assay using purified CHRNA7 and synthetic Arctic A40, and demonstrated that Arctic A40 specifically bound to CHRNA7. The aggregation of Arctic A40 was enhanced with the addition of CHRNA7. Furthermore, the function of CHRNA7 was detected by measuring Ca2+ flux and phospho-p44/42 MAPK (ERK1/2) activation. Our results indicated that Arctic A40 aggregation was enhanced by the addition of CHRNA7, which destabilized the function of CHRNA7 via inhibition of Ca2+ responses and activation of ERK1/2. These findings indicate that Arctic A mutation may be involved in the mechanism underlying FAD. This mechanism may involve binding and aggregation, leading to the inhibition of CHRNA7 functions.

    DOI PubMed

  • A label-free electrical assay of fibrous amyloid beta based on semiconductor biosensing

    Sho Hideshima, Masumi Kobayashi, Takeyoshi Wada, Shigeki Kuroiwa, Takuya Nakanishi, Naoya Sawamura, Toru Asahi, Tetsuya Osaka

    CHEMICAL COMMUNICATIONS   50 ( 26 ) 3476 - 3479  2014

     View Summary

    We propose, as an alternative to conventional spectroscopic assays, a simple method for discriminating fibrous amyloid proteins by using a label-free semiconductor-based biosensor. The highly sensitive assay is expected to be useful for accelerating amyloid related research.

    DOI

  • Construction of photoenergetic mitochondria in cultured mammalian cells

    Kiyotaka Y. Hara, Takeyoshi Wada, Kuniki Kino, Toru Asahi, Naoya Sawamura

    Scientific Reports   3   1635  2013.04

     View Summary

    The proton motive force (PMF) is bio-energetically important for various cellular reactions to occur. We developed PMF-photogenerating mitochondria in cultured mammalian cells. An archaebacterial rhodopsin, delta-rhodopsin, which is a light-driven proton pump derived from Haloterrigena turkmenica, was expressed in the mitochondria of CHO-K1 cells. The constructed stable CHO-K1 cell lines showed suppression of cell death induced by rotenone, a pesticide that inhibits mitochondrial complex I activity involved in PMF generation through the electron transport chain. Delta-rhodopsin was also introduced into the mitochondria of human neuroblastoma SH-SY5Y cells. The constructed stable SH-SY5Y cell lines showed suppression of dopaminergic neuronal cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an inducer of Parkinson's disease models, which acts through inhibition of complex I activity. These results suggest that the light-activated proton pump functioned as a PMF generator in the mitochondria of mammalian cells, and suppressed cell death induced by inhibition of respiratory PMF generation.

    DOI PubMed

  • Construction of new energy synthesis system in SH-SY5Y cells: application for the treatment of Parkinson's disease.

    T. Wada, K. Hara, Y. Asahi, N. Sawamura

    JOURNAL OF NEUROCHEMISTRY   123   24 - 25  2012.10

  • Cereblon accumulates in aggresomes due to proteasome impairment

    S. Wakabayashi, H. Yamada, T. Asahi, N. Sawamura

    JOURNAL OF NEUROCHEMISTRY   123   25 - 25  2012.10

  • Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly

    N. Sawamura, T. Ando, Y. Maruyama, M. Fujimuro, H. Mochizuki, K. Honjo, M. Shimoda, H. Toda, T. Sawamura-Yamamoto, L. A. Makuch, A. Hayashi, K. Ishizuka, N. G. Cascella, A. Kamiya, N. Ishida, T. Tomoda, T. Hai, K. Furukubo-Tokunaga, A. Sawa

    MOLECULAR PSYCHIATRY   13 ( 12 ) 1138 - 1148  2008.12

     View Summary

    Disrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription.

    DOI

  • The fruitfly Drosophila melanogaster: A promising model to explore molecular psychiatry

    N. Sawamura, N. Ishida, T. Tomoda, T. Hai, K. Furukubo-Tokunaga, A. Sawa

    Molecular Psychiatry   13 ( 12 ) 1069 - 1069  2008.12

    DOI

  • Molecules regulated by patterns of electrical activity

    Miwako Ozaki, Naoya Sawamura, Michinori Ichikawa

    NEUROSCIENCE RESEARCH   58   S142 - S142  2007

  • Primate disrupted-in-schizophrenia-1 (DISC1): High divergence of a gene for major mental illnesses in recent evolutionary history

    Lyuda Bord, Jeff Wheeler, Matthew Paek, Masoumeh Saleh, Ariel Lyons-Warren, Christopher A. Ross, Naoya Sawamura, Akira Sawa

    NEUROSCIENCE RESEARCH   56 ( 3 ) 286 - 293  2006.11

     View Summary

    Here we analyze the species conservation of disrupted-in-schizophrenia-1 (DISC1) gene, a susceptibility gene for schizophrenia. We cloned cDNA of DISCI and characterized DISCI protein in monkey brains and compared their features with those in a variety of species, including humans, rodents and lower vertebrates. Sequences of human and monkey DISCI are very similar for both nucleotides and amino acids, in sharp contrast to those of rodents; this is reminiscent of G72, another gene involved in major mental illnesses. Bioinformatic cross-species comparisons identified a portion of DISC] sequences in chicken and Caenorhabditis elegans, but failed to find DISC1 in Drosophila. In contrast to sequence differences, the regional expression profile of DISCI is well conserved between rodents and primates in that levels of DISC I mRNA and protein are higher in the hippocampus and the cerebral cortex, and much lower in cerebellum in adult brains. The findings of this study may suggest overall patterns of evolution of genes for psychiatric disorders, and thus assist in production of genetically-engineered mice, and the interpretation of the underlying mechanisms of psychiatric conditions. Published by Elsevier Ireland Ltd on behalf of Japan Neuroscience Society.

    DOI

  • Disrupted-in-Schizophrenia-1 (DISC1) - A key susceptibility factor for major mental illnesses

    Naoya Sawamura, Akira Sawa

    INTEGRATED MOLECULAR MEDICINE FOR NEURONAL AND NEOPLASTIC DISORDERS   1086   126 - 133  2006

     View Summary

    Here we overview Disrupted-in-Schizophrenia-1 (DISC1), a promising lead in studying the pathophysiology of major mental conditions. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. Different from several other susceptibility genes for schizophrenia, such as neuregulin-1 and dysbindin, there are two independent pedigrees in which genetic variations of DISC1 directly segregate with major mental conditions. This uniqueness has facilitated neurobiology of DISC1, which may hopefully lead to an important breakthrough in understanding of pathophysiology of major mental conditions. DISC1 is a multifunctional protein that plays a role in neurodevelopment and cell signaling. In autopsied brains from patients with psychosis and substance abuse, change in subcellular distribution of DISC1 is observed. DISC1 interacts with phosphodiesterase (PDE) 4B that degrades cyclic AMP (cAMP), which may be a regulatory molecule for working memory in the prefrontal cortex. Knockdown expression of DISC1 in developing cerebral cortex in mouse brains leads to changes that resemble, at least in part, the pathology found in patients with schizophrenia. These results support involvement of DISC1 in the pathophysiology of major mental conditions, including schizophrenia, in several mechanisms.

    DOI

  • 【統合失調症の分子医学】 DISC1からみた統合失調症の分子病態

    疋田 貴俊, 澤村 直哉, 尾関 祐二, 神谷 篤, 澤 明

    細胞   37 ( 14 ) 573 - 576  2005.12

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    統合失調症の病態に複数の遺伝子と環境要因の関与が指摘されている.最近連鎖研究・関連研究からいくつかの統合失調症の候補遺伝子が明らかになってきた.本稿では,そのなかからDISC1(Disrupted-In-Schizophrenia 1)からみた統合失調症の病態研究を展望する.DISC1は精神疾患多発単一家系から発見されたが,遺伝学的研究と統合失調症患者剖検脳を用いた生化学的研究から統合失調症一般例においてもDISC1の統合失調症への関与が示唆されている.DISC1は多くの細胞内部位で働く多機能タンパクであり,特に細胞骨格に関与して神経発達に重要な役割を果たしている.DISC1のさらなる解析,特にDISC1のトランスジェニックマウスによる統合失調症の動物モデルの確立が統合失調症の病態理解や治療法の開発につながることが期待される(著者抄録)

  • A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development

    A Kamiya, K Kubo, T Tomoda, M Takaki, R Youn, Y Ozeki, N Sawamura, U Park, C Kudo, M Okawa, CA Ross, ME Hatten, K Nakajima, A Sawa

    NATURE CELL BIOLOGY   7 ( 12 ) 1167 - 1178  2005.12

     View Summary

    Disrupted-In-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. Schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wildtype DISC1 through self-association and by dissociating the DISC1-dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISCI function may underlie neurodevelopmental dysfunction in schizophrenia.

    DOI

  • DISC1からみた統合失調症の分子病態 (特集 統合失調症の分子医学)

    疋田 貴俊, 澤村 直哉, 尾関 祐二

    細胞   37 ( 14 ) 573 - 576  2005.12

  • Disrupted-In-Schizophrenia-1 (DISC1): A promising lead in molecular analyzes of schizophrenia

    A Sawa, N Sawamura, R Balkissoon

    CLINICAL NEUROSCIENCE RESEARCH   5 ( 1 ) 23 - 30  2005.09

     View Summary

    Although the genetics of schizophrenia (SZ) remains unresolved, recently both linkage/association studies and cytogenetic approaches have clarified several possible genes for SZ. In the neuropathology of SZ, many now agree that there are at least cytoarchitectural abnormalities such as alterations in synaptic, dendritic, and axonal organization, but clear molecular markers unique to SZ are still missing.
    In this review, we propose an approach relying on Disrupted-In-Schizophrenia-1 (DISC1), a candidate gene for SZ that may shed light on the molecular neuropathology of SZ. DISC1 was originally identified as the sole disrupted gene with an open reading frame, from a 'unique' Scottish family in which familial SZ and other major mental illnesses occur in tight association with a hereditary chromosomal abnormality. Additional genetic and biochemical approaches using autopsied brains from patients with SZ from other populations than the Scottish family suggest that DISC1 may be implicated not only in the Scottish family but also in general' cases of SZ. Furthermore. functional dissection of DISC1 protein indicates that DISC1 is a cytoskeletal protein that plays a key role in neurodevelopment, which may be relevant to the pathogenesis of SZ.
    Here, we provide a summary of the current updates of studies of DISC1 and their future perspective, especially its possible role in the pathophysiology of SZ, in association with other genetic and environmental factors. (c) 2005 Association for Research in Nervous and Mental Disease. Published by Elsevier B.V. All rights reserved.

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  • Production of DISC1 transgenic and knockout mice

    T Hikida, N Sawamura, M Paek, M Cascio, A Sawa

    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS   138B ( 1 ) 134 - 135  2005.09

  • A form of DISC1 enriched in nucleus: Altered subcellular distribution in orbitofrontal cortex in psychosis and substance/alcohol abuse

    N Sawamura, T Sawamura-Yamamoto, Y Ozeki, CA Ross, A Sawa

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   102 ( 4 ) 1187 - 1192  2005.01  [Refereed]

     View Summary

    Disrupted-In-Schizophrenia 1 (DISC1) was identified as the sole gene whose ORF is truncated and cosegregates with major mental illnesses in a Scottish family. DISC1 has also been suggested, by association and linkage studies, to be a susceptibility gene for schizophrenia (SZ) in independent populations. However, no analysis of DISC1 protein in human brains, especially those of patients with SZ, has yet been conducted. Here we performed a biochemical analysis of DISC1 protein in a well characterized set of autopsied brains, including brains of patients with SZ, bipolar disorder, and major depression (MD), as well as normal control brains. We identified an isoform of DISC1 by using MS and demonstrated that it is enriched in the nucleus of HeLa cells. In the orbitofrontal cortex, the subcellular distribution of this DISC1 isoform, assessed by the nuclear to cytoplasmic ratio in the immunoreactivity of the isoform, is significantly changed in brains from patients with SZ and MD. This altered distribution is also observed in those subjects with substance and alcohol abuse. The changes in MD brains are significantly influenced by substance/alcohol abuse as well as postmortem interval; however, the alteration in SZ brains is free from brain-associated confounding factors, although an interaction with substance/alcohol abuse cannot be completely ruled out. These results suggest that DISC1 may be implicated in psychiatric conditions in other populations than the unique Scottish family.

    DOI PubMed

  • A form of Disrupted-In-Schizophrenia-1 (DISC1) enriched in the nucleus has altered subcellular distribution in schizophrenia brains.

    Sawamura N, Sawamura-Yamamoto T, Ozeki Y, Ross C.A, Sawa A

    Proceedings of the National Academy of Sciences   102   1187 - 1192  2005

  • Modulation of amyloid precursor protein cleavage by cellular sphingolipids

    N Sawamura, MH Ko, WX Yu, K Zou, K Hanada, T Suzuki, JS Gong, K Yanagisawa, M Michikawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   279 ( 12 ) 11984 - 11991  2004.03

     View Summary

    Lipid rafts and their component, cholesterol, modulate the processing of beta-amyloid precursor protein (APP). However, the role of sphingolipids, another major component of lipid rafts, in APP processing remains undetermined. Here we report the effect of sphingolipid deficiency on APP processing in Chinese hamster ovary cells treated with a specific inhibitor of serine palmitoyltransferase, which catalyzes the first step of sphingolipid biosynthesis, and in a mutant LY-B strain defective in the LCB1 subunit of serine palmitoyltransferase. We found that in sphingolipid-deficient cells, the secretion of soluble APPalpha (sAPPalpha) and the generation of C-terminal fragment cleaved at alpha-site dramatically increased, whereas epsilon-cleavage activity remained unchanged, and the epsilon-cleavage activity decreased without alteration of the total APP level. The secretion of amyloid beta-protein 42 increased in sphingolipid-deficient cells, whereas that of amyloid beta-protein 40 did not. All of these alterations were restored in sphingolipid-deficient cells by adding exogenous sphingosine and in LY-B cells by transfection with cLCB1. Sphingolipid deficiency increased MAPK/ERK activity and a specific inhibitor of MAPK kinase, PD98059, restored sAPPalpha level, indicating that sphingolipid deficiency enhances sAPPalpha secretion via activation of MAPK/ERK pathway. These results suggest that not only the cellular level of cholesterol but also that of sphingolipids may be involved in the pathological process of Alzheimer's disease by modulating APP cleavage.

    DOI

  • 【脳・神経研究2004 神経発生・可塑性と高次脳機能のメカニズム,そして脳・神経疾患の分子機構の解明へ】 脳神経機能障害・疾患研究 統合失調症とDISC1

    澤村 直哉, 澤 明

    実験医学   21 ( 17 ) 2469 - 2473  2003.11

     View Summary

    統合失調症は思春期に好発する難治性の精神疾患である.その有病率は人口の1%に及び,継続的な医療が必要にも拘わらず,社会復帰や根治が困難であることから,その病態の把握は急務となっている.こうした中,遺伝学的検索から発見されたDisrupted-In-Schizophrenia 1(DISC1)は,精神疾患研究でおそらく最初にみとめられた候補遺伝子であり,このDISC1及びその遺伝子産物の解析を進めることにより,その病態に迫ることができるのではないかと現在期待されている

  • Amyloid beta-protein (A beta)1-40 protects neurons from damage induced by A beta 1-42 in culture and in rat brain

    K Zou, D Kim, A Kakio, K Byun, JS Gong, J Kim, M Kim, N Sawamura, S Nishimoto, K Matsuzaki, B Lee, K Yanagisawa, M Michikawa

    JOURNAL OF NEUROCHEMISTRY   87 ( 3 ) 609 - 619  2003.11

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    Previously, we found that amyloid beta-protein (Abeta)1-42 exhibits neurotoxicity, while Abeta1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Abeta1-40 against Abeta1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Abeta1-42 at concentrations higher than 2 mum, which was prevented by concurrent treatment with Abeta1-40 in a dose-dependent manner. However, metal chelators did not prevent Abeta1-42-induced neuronal death. Circular dichroism spectroscopy showed that Abeta1-40 inhibited the beta-sheet transformation of Abeta1-42. Thioflavin-T assay and electron microscopy analysis revealed that Abeta1-40 inhibited the fibril formation of Abeta1-42. In contrast, Abeta1-16, Abeta25-35, and Abeta40-1 did not inhibit the fibril formation of Abeta1-42 nor prevent Abeta1-42-induced neuronal death. Abeta1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Abeta1-40. These results indicate that Abeta1-40 protects neurons from Abeta1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the beta-sheet transformation and fibril formation of Abeta1-42. Our data suggest a mechanism by which elevated Abeta1-42/Abeta1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.

    DOI

  • Promotion of tau phosphorylation by MAP kinase Erk1/2 is accompanied by reduced cholesterol level in detergent-insoluble membrane fraction in Niemann-Pick C1-deficient cells

    N Sawamura, JS Gong, TY Chang, K Yanagisawa, M Michikawa

    JOURNAL OF NEUROCHEMISTRY   84 ( 5 ) 1086 - 1096  2003.03

     View Summary

    Niemann-Pick type C (NPC) disease is a cholesterol-storage disease accompanied by neurodegeneration with the formation of neurofibrillary tangles, the major component of which is the hyperphosphorylated tau. Here, we examined the mechanism underlying hyperphosphorylation of tau using mutant Chinese hamster ovary (CHO) cell line defective in NPC1 (CT43) as a tool. Immunoblot analysis revealed that tau was hyperphosphorylated at multiple sites in CT43 cells, but not in their parental cells (25RA) or the wild-type CHO cells. In CT43 cells, mitogen-activated protein (MAP) kinase Erk1/2 was activated and the specific MAPK inhibitor, PD98059, attenuated the hyperphosphorylation of tau. The amount of protein phosphatase 2A not bound to microtubules was decreased in CT43 cells. CT43 cells but not 25RA cells were amphotericin B-resistant, indicating that cholesterol level in the plasma membrane of CT43 is decreased. In addition, the level of cholesterol in the detergent-insoluble, low-density membrane (LDM) fraction of CT43 cells was markedly reduced compared with the other two types of CHO cells. As LDM domain plays critical role in signaling pathways, these results suggest that the reduced cholesterol level in LDM domain due to the lack of NPC1 may activate MAPK, which subsequently promotes tau phosphorylation in NPC1-deficient cells.

    DOI

  • 統合失調症とDISC1

    澤村 直哉, 澤 明

    実験医学 -脳・神経研究2004, 増刊-   21   2469 - 2473  2003

  • Amyloid beta-protein affects cholesterol metabolism in cultured neurons: Implications for pivotal role of cholesterol in the amyloid cascade

    JS Gong, N Sawamura, K Zou, J Sakai, K Yanagisawa, M Michikawa

    JOURNAL OF NEUROSCIENCE RESEARCH   70 ( 3 ) 438 - 446  2002.11

     View Summary

    Recently, we have found that alterations in cellular cholesterol metabolism are involved in promotion of tau phosphorylation (Fan et al. [2001] J. Neurochem. 76: 391-400; Sawamura et al. [2001] J. Biol. Chem. 276:10314-10319). In addition, we have shown that amyloid beta-protein (Abeta) promotes cholesterol release to form Abeta-lipid particles (Michikawa et al. [2001] J. Neurosci. 21:7226-7235). These lines of evidence inspired us to conduct further studies on whether Abeta affects cholesterol metabolism in neurons, which might lead to tau phosphorylation. Here, we report the effect of Abeta1-40 on cholesterol metabolism in cultured neurons prepared from rat cerebral cortex. Oligomeric Abeta1-40 inhibited cholesterol synthesis and reduced cellular cholesterol levels in a dose- and time-dependent manner, while freshly dissolved Abeta had no effect on cholesterol metabolism. However, oligomeric Abeta had no effect on the proteolysis of sterol regulatory element binding protein-2 (SREBP-2) or protein synthesis in cultured neurons. Oligomeric Abeta did not enhance lactate dehydrogenase (LDH) release from neuronal cells or decrease signals in the cultures reactive to 3,3'-Bis[N,N-bis(carboxymethyl)aminomethyl]fluorescein, hexaacetoxymethyl ester (calcein AM) staining, indicating that Abeta used in this experiment did not cause neuronal death during the time course of our experiments. Since alterations in cholesterol metabolism induce tau phosphorylation, our findings that oligomeric Abeta alters cellular cholesterol homeostasis may provide new insight into the mechanism underlying the amyloid cascade hypothesis. (C) 2002 Wiley-Liss, Inc.

    DOI

  • Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice

    JS Gong, M Kobayashi, H Hayashi, K Zou, N Sawamura, SC Fujita, K Yanagisawa, M Michikawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   277 ( 33 ) 29919 - 29926  2002.08

     View Summary

    We have reported previously (Michikawa, M., Fan, Q.-W., Isobe, I., and Yanagisawa, K. (2000) J. Neurochem. 74, 1008-1016) that exogenously added recombinant human apolipoprotein E (apoE) promotes cholesterol release in an isoform-dependent manner. However, the molecular mechanism underlying this isoform-dependent promotion of cholesterol release remains undetermined. In this study, we demonstrate that the cholesterol release is mediated by endogenously synthesized and secreted apoE isoforms and clarify the mechanism underlying this apoE isoform-dependent cholesterol release using cultured astrocytes prepared from human apoE3 and apoE4 knock-in mice. Cholesterol and phospholipids were released into the culture media, resulting in the generation of two types of high density lipoprotein (HDL)-like particles; one was associated with apoE and the other with apoJ. The amount of cholesterol released into the culture media from the apoE3-expressing astrocytes was similar to2.5-fold greater than that from apoE4-expressing astrocytes. In contrast, the amount of apoE3 released in association with the HDL-like particles was similar to that of apoE4, and the sizes of the HDL-like particles released from apoE3- and apoE4-expressing astrocytes were similar. The molar ratios of cholesterol to apoE in the HDL fraction of the culture media of apoE3- and apoE4-expressing astrocytes were 250 +/- 6.0 and 119 +/- 5.1, respectively. These data indicate that apoE3 has an ability to generate similarly sized lipid particles with less number of apoE molecules, than apoE4, suggesting that apoE3-expressing astrocytes can supply more cholesterol to neurons than apoE4-expressing astrocytes. These findings provide a new insight into the issue concerning the putative alteration of apoE-related cholesterol metabolism in Alzheimer's disease.

    DOI

  • Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons (vol 80, pg 178, 2002)

    QW Fan, W Yu, JS Gong, K Zou, N Sawamura, T Senda, K Yanagisawa, M Michikawa

    JOURNAL OF NEUROCHEMISTRY   80 ( 5 ) 940 - 940  2002.03

    DOI

  • A novel action of Alzheimer's amyloid beta-protein (A beta): Oligomeric A beta promotes lipid release

    M Michikawa, JS Gong, QW Fan, N Sawamura, K Yanagisawa

    JOURNAL OF NEUROSCIENCE   21 ( 18 ) 7226 - 7235  2001.09

     View Summary

    Interactions between amyloid beta -protein (A beta) and lipids have been suggested to play important roles in the pathogenesis of Alzheimer's disease. However, the molecular mechanism underlying these interactions has not been fully understood. We examined the effect of A beta on lipid metabolism in cultured neurons and astrocytes and found that oligomeric A beta, but not monomeric or fibrillar A beta, promoted lipid release from both types of cells in a dose- and time-dependent manner. The main components of lipids released after the addition of A beta were cholesterol, phospholipids, and monosialoganglioside (GM1). Density-gradient and electron microscopic analyses of the conditioned media demonstrated that these A beta and lipids formed particles and were recovered from the fractions at densities of similar to1.08-1.18 g/ml, which were similar to those of high-density lipoprotein (HDL) generated by apolipoproteins. The lipid release mediated by A beta was abolished by concomitant treatment with Congo red and the PKC inhibitor, H7, whereas it was not inhibited with N-acetyl-L-cysteine. These A beta -lipid particles were not internalized into neurons, whereas HDL-like particles produced by apolipoprotein E were internalized. Our findings indicate that oligomeric A beta promotes lipid release from neuronal membrane, which may lead to the disruption of neuronal lipid homeostasis and the loss of neuronal function.

  • Site-specific phosphorylation of tau accompanied by activation of mitogen-activated protein kinase (MAPK) in brains of Niemann-Pick type C mice

    N Sawamura, JS Gong, WS Garver, RA Heidenreich, H Ninomiya, K Ohno, K Yanagisawa, M Michikawa

    JOURNAL OF BIOLOGICAL CHEMISTRY   276 ( 13 ) 10314 - 10319  2001.03

     View Summary

    Niemann-Pick type C (NPC) disease is characterized by an accumulation of cholesterol in most tissues and progressive neurodegeneration with the formation of neurofibrillary tangles. Neurofibrillary tangles are composed of paired helical filaments (PHF), a major component of which is the hyperphosphorylated tau. In this study we used NPC heterozygous and NPC homozygous mouse brains to investigate the molecular mechanism responsible for tauopathy in NPC, Immunoblot analysis using anti-tau antibodies (Tau-1, PHF-1, AT-180, and AT-100) revealed site-specific phosphorylation of tau at Ser-396 and Ser-404 in the brains of NPC homozygous mice. Mitogen-activated protein kinase, a potential serine kinase known to phosphorylate tau, was activated, whereas other serine kinases such as glycogen synthase kinase-3 beta and cyclin-dependent kinase 5 were inactive. Morphological examination demonstrated that a number of neurons the perikarya of which strongly immunostained with PHF-1, exhibited polymorphorous cytoplasmic inclusion bodies and multi-concentric lamellar-like bodies. Importantly, the accumulation of intracellular cholesterol in NPC mouse brains was determined to be a function of age. From these results we conclude that abnormal cholesterol metabolism due to the genetic mutation in NPC1 may be responsible for activation of the mitogen-activated protein kinase-signaling pathway and site-specific phosphorylation of tau in vivo, leading to tauopathy in NPC.

    DOI

  • Mutant presenilin 2 transgenic mice - A large increase in the levels of A beta 42 id presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin

    N Sawamura, M Morishima-Kawashima, H Waki, K Kobayashi, T Kuramochi, MP Frosch, K Ding, M Ito, TW Kim, RE Tanzi, F Oyama, T Tabira, S Ando, Y Ihara

    JOURNAL OF BIOLOGICAL CHEMISTRY   275 ( 36 ) 27901 - 27908  2000.09

     View Summary

    The N141I mutation in presenilin (PS) 2 is tightly linked with a form of autosomal dominant familial Alzheimer's disease in the Volga German families. We previously reported that mouse brains harboring mutant PS2 contained increased levels of amyloid beta protein (A beta) 42 in the Tris-saline-soluble fraction (Oyama, F., Sawamura, N., Kobayashi, K., Morishima-Kawashima, M., Kuramochi, T., Ito, M., Tomita, T., Maruyama, K., Saido, T. C., Iwatsubo, T., Capell, A., Waiter, J., Grunberg, J., Ueyama, Y., Haass, C. and Ihara, Y. (1998) J. Neurochem. 71, 313-322). Here, using a new extraction protocol, we quantitated the A beta 40 and A beta 42 levels in the Tris-saline-insoluble fraction. The insoluble A beta levels were found to be higher than the soluble A beta levels, and the insoluble A beta 42 levels were markedly increased in mutant PS2 transgenic mice. To investigate the origin of the insoluble A beta 42, we prepared the detergent-insoluble, low density membrane fraction. This fraction from two independent lines of mutant PS2 transgenic mice contained remarkably increased levels of A beta 42 and significantly low levels of glycerophospholipids and sphingomyelin. This unexpected finding suggests that a large increase in the levels of A beta 42 in mutant PS2 mice is presumably induced through alterations of the lipid composition in the low density membrane domain in the brain.

    DOI

  • Mutant presenilin 2 transgenic mouse: Effect on an age-dependent increase of amyloid beta-protein 42 in the brain

    F Oyama, N Sawamura, K Kobayashi, M Morishima-Kawashima, T Kuramochi, M Ito, T Tomita, K Maruyama, TC Saido, T Iwatsubo, A Capell, J Walter, L Grunberg, Y Ueyama, C Haass, Y Ihara

    JOURNAL OF NEUROCHEMISTRY   71 ( 1 ) 313 - 322  1998.07

     View Summary

    The N141I missense mutation in presenilin (PS) 2 is tightly linked with a form of autosomal dominant familial Alzheimer's disease (AD) in the Volga German families. We have generated transgenic mouse lines overexpressing human wild-type or mutant PS2 under transcriptional control of the chicken beta-actin promoter. In the brains of transgenic mice, the levels of human PS2 mRNA were found to be five-to 15-fold higher than that of endogenous mouse PS2 mRNA, The amyloid beta-protein (AP) 42 levels in the brains of mutant PS2 transgenic mice were higher than those in wild-type PS2 transgenic mice at the age of 2, 5, or 8 months. In addition, the A beta 42 levels appeared to increase steadily in the mutant PS2 transgenic mouse brains from 2 to 8 months of age, whereas there was only a small increase in wild-type transgenic mice between the ages of 5 and 8 months. There was no definite difference in the levels of N-terminal and C-terminal fragments between wild-type and mutant PS2 transgenic mice at the age of 2, 5, or 8 months. These data show a definite effect of the PS2 mutation on an age-dependent increase of A beta 42 content in the brain.

    DOI

  • Deposition of amyloid beta protein (A beta) subtypes [A beta 40 and A beta 42(43)] in canine senile plaques and cerebral amyloid angiopathy

    S Nakamura, A Tamaoka, N Sawamura, W Kiatipattanasakul, H Nakayama, S Shoji, Y Yoshikawa, K Doi

    ACTA NEUROPATHOLOGICA   94 ( 4 ) 323 - 328  1997.10

     View Summary

    To clarify the immunohistochemical features of canine senile plaques (SPs) and cerebral amyloid angiopathy (CAA), the distribution of the amyloid beta protein (A beta) subtypes A beta 40 and A beta 42(43), A beta precursor protein (APP), and glial cell reaction were examined in the brains of seven aged dogs (12-18 years). A beta 42(43) was found to be deposited in all types of SPs, whereas A beta 40 was deposited only in mature (classical and primitive) plaques. CAA, which was located along parenchymal and meningeal arterioles and capillaries, consisted of both subtypes of A beta. APP was exhibited in normal and degenerative neurons and swollen neurites of mature plaques. It was, therefore, considered that A beta 42(43) in diffuse plaques might be derived from APP in neurons, while A beta 40 and A beta 42(43) in mature plaques might be generated from APP in swollen neurites in the plaque. In contrast to the case in humans, in whom deposition of A beta 40 and A beta 42(43) in the mature plaques is predominantly associated with microglial reaction, in dogs we found that it was closely associated with astroglial reaction. The present findings showed characteristics of canine SPs which are different from those of humans.

    DOI

  • Characterization of amyloid beta protein species in cerebral amyloid angiopathy of a squirrel monkey by immunocytochemistry and enzyme-linked immunosorbent assay

    N Sawamura, A Tamaoka, S Shoji, EH Koo, LC Walker, H Mori

    BRAIN RESEARCH   764 ( 1-2 ) 225 - 229  1997.08

     View Summary

    We analyzed the composition of amyloid beta protein (A beta) species in cerebral amyloid angiopathy (CAA) of an aged squirrel monkey. Immunocytochemistry demonstrated that the cerebral cortex contained no lesions other than widespread CAA with A beta 40 as its apparent major component. However, enzyme-linked immunosorbent assay revealed that A beta 42(43) predominated over A beta 40 in a formic acid-extracted cortical fraction. These findings suggest possible underestimation of A beta 42(43) levels in some previous immunocytochemical investigations. (C) 1997 Elsevier Science B.V.

    DOI

  • Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease

    A Tamaoka, N Sawamura, T Fukushima, S Shoji, E Matsubara, M Shoji, S Hirai, Y Furiya, R Endoh, H Mori

    JOURNAL OF THE NEUROLOGICAL SCIENCES   148 ( 1 ) 41 - 45  1997.05

     View Summary

    To investigate the pathomechanism of amyloid beta protein (A beta) deposition in brains with Alzheimer's disease (AD), cerebrospinal fluid (CSF) levels of A beta species (CSF-A beta) with different carboxy termini, i.e. A beta X-40 and A beta X-42(43) as well as A beta 1-40 and A beta 1-42(43), were measured in patients with AD and age-matched controls without dementia (CTR) using sandwich enzyme-linked immunosorbent assays (ELISAs). The present study revealed that both CSF-A beta X-42(43) and A beta 1-42(43) levels were significantly lower in the AD patients (P<0.005) than in the CTR group, whereas neither CSF-A beta X-40 nor CSF-A beta 1-40 levels showed any differences between the two groups. In addition, although there was no difference between the ratios of A beta X-40 to A beta 1-40 in the AD and CTR groups, the ratios of A beta X-42(43) to A beta 1-42(43) were increased in the AD group compared with those in the CTR group (P<0.05). Therefore, it can be assumed that the ratios of amino terminal truncations and/or modifications of CSF-A beta 42(43) with carboxy termini ending at residue 42(43) were more increased in the AD group than in the CTR group. Increased adsorption of A beta 42(43) to A beta deposition in AD brains, decreased secretion of A beta 42(43) to CSF and/or increased clearance of A beta 42(43) from CSF might explain the diminished levels of A beta 42(43) in the CSF of AD patients. In addition, CSF-A beta 42(43) could reflect increased amino terminal truncations and/or modifications of A beta 42(43) in AD brains. (C) 1997 Elsevier Science B.V.

    DOI

  • Amyloid beta protein in plasma from patients with sporadic Alzheimer's disease

    A Tamaoka, T Fukushima, N Sawamura, K Ishikawa, E Oguni, Y Komatsuzaki, S Shoji

    JOURNAL OF THE NEUROLOGICAL SCIENCES   141 ( 1-2 ) 65 - 68  1996.09

     View Summary

    Fibrillar amyloid beta protein (A beta) deposition is increased in the brains of patients with Alzheimer's disease (AD), and is manifested as senile plaques (SPs) and congophilic angiopathy (CA). A beta 40 and A beta 42(43), two chief species of A beta, are documented in SPs and CA, as well as in cerebrospinal fluid (CSF) and cell culture media. A beta 42(43) is the major component of diffuse plaques, the earliest form of SPs. Thus, we hypothesized that determination of the amount of A beta 42(43) in CSF or plasma might provide a diagnostic laboratory test for AD. We measured amounts of different A beta species in plasma from 28 patients with sporadic probable AD, 40 age-matched neurologic patients without dementia and 25 age-matched normal controls using enzyme-linked immunosorbent assays (ELISAs). Plasma concentrations of A beta 1-40 and A beta 1-42(43) did not significantly differ among these groups. These findings suggest the unlikelihood that plasma A beta assays would be useful as a diagnostic tool for AD.

    DOI

  • Carboxyl end-specific monoclonar antibodies to amyloid beta protein (A beta) subtypes (A beta 40 and A beta 42(43)) differentiate A beta in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys

    S Nakamura, A Tamaoka, N Sawamura, S Shoji, H Nakayama, F Ono, Sakakibara, I, Y Yoshikawa, H Mori, N Goto, K Doi

    NEUROSCIENCE LETTERS   201 ( 2 ) 151 - 154  1995.12

     View Summary

    Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) in the brains of five aged (20-26 years old) cynomolgus monkeys were investigated immunohistochemically using two monoclonal antibodies (anti-A beta 40 (BA27) and anti-A beta 42(43) (BC05)) that can differentiate the carboxyl termini of amyloid beta protein (A beta) subtypes. In four of five animals, all types of SPs (i.e. diffuse, primitive, and classical plaques; DPs, PPs, and CPs, respectively) were identified by BC05. However, BA27 did not label DPs and stained only about one third of PPs and CPs, mainly labeling granular structures and cored portions, respectively. In CAA, lesions of cortical capillaries reacted to BC05 in four of five cases, but rarely and weakly to BA27 in two of five cases. On the other hand, lesions of parenchymal and meningeal arterioles were stained by both BA27 and BC05. These staining profiles of SPs in cynomolgus monkeys correspond well to those in humans, although there are two remarkable features in cynomolgus monkeys. First, BA27 stained PPs associated with granular structures. Secondly, capillary A beta reacted intensely to BC05 but only slightly to BA27. Despite these unique features, the results suggest that aged cynomolgus monkeys can be used to investigate the pathogenesis of A beta deposition in SPs and CAA.

    DOI

  • AMYLOID-BETA PROTEIN-1-42/43 (A-BETA-1-42/43) IN CEREBELLAR DIFFUSE PLAQUES - ENZYME-LINKED-IMMUNOSORBENT-ASSAY AND IMMUNOCYTOCHEMICAL STUDY

    A TAMAOKA, N SAWAMURA, A ODAKA, N SUZUKI, H MIZUSAWA, S SHOJI, H MORI

    BRAIN RESEARCH   679 ( 1 ) 151 - 156  1995.05

     View Summary

    Diffuse plaques are immature and amorphous senile plaques and believed to be in the initial phase of plaque formation. In contrast to amyloid angiopathy and the plaque core amyloid, diffuse plaques failed to be purified in preserved forms from the brain. Here, we studied the diffuse plaques in the cerebellar region of the Alzheimer's disease brain based on immunocytochemistry and ELISA using two different monoclonal antibodies specifically recognizing the carboxyl termini of A beta molecules (BA27 for A beta 1-40 and BC05 for A beta 1-42/43). We found that the amount of A beta 1-40 was in proportion to the staining degree on amyloid angiopathy by immunohistochemistry. We found that A beta 1-42/43 comprised diffuse plaques as the major component in the cerebella of AD brains. Taking these findings into consideration, diffuse plaques, the earliest pathological change in the brain with AD, are concluded to be composed mainly of A beta 1-42/43, implicating the critical importance of this kind of A beta species deposition in the pathogenesis of AD.

    DOI

  • BIOCHEMICAL-EVIDENCE FOR THE LONG-TAIL FORM (A-BETA-1-42-43) OF AMYLOID-BETA PROTEIN AS A SEED MOLECULE IN CEREBRAL DEPOSITS OF ALZHEIMERS-DISEASE

    A TAMAOKA, T KONDO, A ODAKA, N SAHARA, N SAWAMURA, K OZAWA, N SUZUKI, S SHOJI, H MORI

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   205 ( 1 ) 834 - 842  1994.11

     View Summary

    We measured the amounts of total A beta, A beta 1-40, and A beta 1-42/43 in brain tissues using a newly developed ELISA assay and found that the amounts of insoluble A beta 1-42/43 and insoluble A beta 1-40) were linearly related to the amount of A beta deposits or total insoluble A beta at their lon er and higher concentrations, respectively. In an experiment to characterize the A beta species in brain homogenates with buffered saline, we unexpectedly detected soluble AB which was derived from the insoluble amyloid deposits in brain tissue, indicating reversible depolymerisation of AR from insoluble amyloid deposits. To confirm this finding, we performed 5 consecutive washes of insoluble precipitates of AD brains with buffered saline. Bath species of A beta were found in all 5 supernatant fractions and their amounts were gradually decreased. The ratio of A beta 1-42/43/43 to A beta-40 was increased with the numbers of washes, indicating that A beta 1-42/43) existed in an exposed manner as compared to A beta 1-42/43. Thus the present finding is the first biochemical evidence that A beta 1-40, was the predominant species involved in the reversible exchanging reaction on seeding A beta 1-42/43 between the soluble and the insoluble forms (amyloid fibrils). (C) 1994 Academic Press, Inc.

    DOI

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Books and Other Publications

  • 生命科学概論 第2版

    澤村 直哉

    2019.03

  • 生命科学概論

    澤村直哉, 朝日透 他

    朝倉書店  2012.04

  • KEYWORD 精神第4版

    澤村 直哉, 尾崎美和子

    先端医学社  2007

Misc

  • 微小管結合タンパク質タウの分子進化解析

    高田海冴, 小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web)   23rd  2021

    J-GLOBAL

  • 遠縁な種に対して有効な焼きなまし法による分子系統樹構築法の提案

    小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web)   23rd  2021

    J-GLOBAL

  • An annealing method can effectively construct phylogenetic tree among distantly related sequences

    小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web)   44th  2021

    J-GLOBAL

  • E3 ubiquitin ligase cereblon regulates ER stress-induced abnormal glycogen accumulation.

    川崎晃太郎, 飯田万由花, 川井聡子, 小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web)   44th  2021

    J-GLOBAL

  • 哺乳類APLP1のシナプス接着因子としての進化可能性

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web)   42nd  2019

    J-GLOBAL

  • APPファミリーの分子進化解析により明らかになったAPLP1の神経系に特殊化した進化

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web)   21st  2019

    J-GLOBAL

  • DETECTION OF AMYLOID β WITH DIFFERENT AGGREGATE MORPHOLOGY BY USING FIELD EFFECT TRANSISTORS

    小林万純, 秀島翔, 黒岩繁樹, 中西卓也, 澤村直哉, 朝日透, 朝日透, 逢坂哲彌, 逢坂哲彌

    Chemical Sensors   29 ( Supplement A )  2013

    J-GLOBAL

  • 電界効果トランジスタを用いた凝集形態の異なるアミロイドβの検出

    小林万純, 秀島翔, 黒岩繁樹, 中西卓也, 澤村直哉, 朝日透, 逢坂哲彌, 朝日透, 逢坂哲彌

    電気化学会大会講演要旨集   80th  2013

    J-GLOBAL

  • ニューレグリンの切断機構に着目した統合失調症発症の分子メカニズムの解明

    澤村直哉

    上原記念生命科学財団研究報告集(CD-ROM)   22   ROMBUNNO.101 - 4  2008.12

     View Summary

    膜貫通型タンパク質であるニューレグリン(NRG)1の切断異常により、統合失調症をはじめとする精神神経疾患発症に至るという仮説のもとに、分子生物学生化学的手法によりNRG1の切断機構を解明することにより、統合失調症をはじめとする精神神経疾患の創薬ターゲットの同定を目指して研究した。NRG1の断片を認識する抗体を用いて免疫沈降法を行い、NRG断片の濃縮精製を試みた。NRG1を発現した大量の細胞のライセートに抗体とプロテインAセファロースを混ぜて反応させた。熱処理によりサンプルを回収し、電気泳動を行い、ゲルから目的の断片を回収した。NRG1タンパクの断片を抗NRG1抗体による免疫沈降法により精製することに成功した。

    J-GLOBAL

  • スフィンゴ脂質によるアミロイド前駆体蛋白の代謝制御

    澤村 直哉, 高 美姫, 于 文新, ゾウ・クン, 花田 賢太郎, 鈴木 利治, きょう 建生, 柳澤 勝彦, 道川 誠

    Dementia Japan   18 ( 2 ) 134 - 134  2004.08

  • 痴呆研究と創薬の展望 アルツハイマー病中核病変とコレステロール

    柳澤 勝彦, 道川 誠, 范 企文, 澤村 直哉, 松崎 勝巳

    基礎老化研究   26 ( 1 ) 6 - 6  2002.04

  • Erratum: Cholesterol-dependent modulation of dendrite outgrowth and microtubule stability in cultured neurons (Journal of Neurochemistry (80) (178-190))

    Qi-Wen Fan, Wei Yu, Jian-Sheng Gong, Kun Zou, Naoya Sawamura, Takao Senda, Katsuhiko Yanagisawa, Makoto Michikawa

    Journal of Neurochemistry   80 ( 5 ) 940  2002

    DOI

  • 脂質代謝とアルツハイマー病の分子病理

    柳澤 勝彦, 道川 誠, 林 秀樹, 澤村 直哉, 松崎 勝巳

    神経化学   40 ( 2-3 ) 220 - 220  2001.09

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Industrial Property Rights

Awards

  • 上原記念生命科学財団 研究奨励金

    2007  

  • National Alliance for Research on Schizophrenia & Depression (NARSAD), Young Investigator Award

    2005  

Research Projects

  • Functional analysis of CHRNA7, a candidate gene product for schizophrenia

  • Arctic AβによるCHRNA7を介したアルツハイマー病発症の分子メカニズム

    科学研究費助成事業(早稲田大学)  科学研究費助成事業(基盤研究(C))

Presentations

  • E3 ubiquitin ligase cereblon regulates ER stress-induced abnormal glycogen accumulation.

    川崎晃太郎, 飯田万由花, 川井聡子, 小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2021

    Event date:
    2021
     
     
  • An annealing method can effectively construct phylogenetic tree among distantly related sequences

    小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2021

    Event date:
    2021
     
     
  • 遠縁な種に対して有効な焼きなまし法による分子系統樹構築法の提案

    小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web) 

    Presentation date: 2021

    Event date:
    2021
     
     
  • 微小管結合タンパク質タウの分子進化解析

    高田海冴, 小野寺航, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web) 

    Presentation date: 2021

    Event date:
    2021
     
     
  • APPファミリーの分子進化解析により明らかになったAPLP1の神経系に特殊化した進化

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web) 

    Presentation date: 2019

    Event date:
    2019
     
     
  • 哺乳類APLP1のシナプス接着因子としての進化可能性

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2019

    Event date:
    2019
     
     
  • E3ユビキチンリガーゼ複合体構成因子Cereblonの分子進化速度解析による機能的残基の同定と機能解析

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web) 

    Presentation date: 2018.08

  • 重度精神遅滞を引き起こすC391R Cereblonの分子機構

    川谷友郎, 朝日透, 朝日透, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2018

  • 光遺伝学的手法の導入はパーキンソン病モデルショウジョウバエのドーパミン神経活動を改善する

    井下強, 孟紅蕊, 原清敬, 澤村直哉, 澤村直哉, 今居譲, 今居譲, 服部信孝, 服部信孝, 服部信孝

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2018

  • Cereblonによるアミロイド前駆体タンパク質の分解機構の解析

    栗原知隆, 朝日透, 朝日透, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2018

  • 分子進化速度解析によるAPPファミリーの差別化された機能の推定

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2018

  • 哺乳類Cereblonの分子進化速度解析による新規機能的サイトの同定

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本生化学会大会(Web) 

    Presentation date: 2017.12

  • 精神遅滞原因候補遺伝子cereblonの分子進化速度解析による機能的サイトの解明

    小野寺航, 朝日透, 朝日透, 澤村直哉

    日本進化学会大会プログラム・講演要旨集(Web) 

    Presentation date: 2017.08

  • CereblonのLonプロテアーゼとしての機能解析

    片岡孝介, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2016

  • CereblonによるMeis2の転写制御機構の解析

    定方春樹, 和田丈慶, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2016

  • 小胞体ストレスに着目したセレブロンの機能解析

    川井聡子, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2016

  • サリドマイドの脳虚血に対する神経保護効果の分子メカニズム

    藤原美紅, 山田まりこ, 林秀樹, 山田春佳, 高木教夫, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本分子生物学会年会プログラム・要旨集(Web) 

    Presentation date: 2016

  • CereblonのLonプロテアーゼとしての役割

    片岡孝介, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本ミトコンドリア学会年会要旨集 

    Presentation date: 2015.11

  • サリドマイドによるエナンチオ特異的なAMPK活性調節メカニズムの解明

    藤原美紅, 山田春佳, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2015.06

  • 精神遅滞候補遺伝子産物セレブロンのアグリソームへの集積と細胞死保護効果

    松本広大, 松本広大, 若林慧, 山田春佳, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本細胞生物学会大会要旨集 

    Presentation date: 2015.06

  • 精神遅滞候補遺伝子産物セレブロンのミトコンドリアにおける機能解析

    片岡孝介, 朝日透, 朝日透, 澤村直哉, 澤村直哉

    日本細胞生物学会大会要旨集 

    Presentation date: 2015.06

  • イオンビームを用いたAu2+導入による生細胞への影響検証

    野間口達洋, 坂口雄紀, 澤村直哉, 谷井孝至, 品田賢宏, 朝日透

    応用物理学会春季学術講演会講演予稿集(CD-ROM) 

    Presentation date: 2014.03

  • 電界効果トランジスタを用いた凝集形態の異なるアミロイドβの検出

    小林万純, 秀島翔, 黒岩繁樹, 中西卓也, 澤村直哉, 朝日透, 逢坂哲彌

    電気化学会大会講演要旨集 

    Presentation date: 2013.03

  • DETECTION OF AMYLOID β WITH DIFFERENT AGGREGATE MORPHOLOGY BY USING FIELD EFFECT TRANSISTORS

    小林万純, 秀島翔, 黒岩繁樹, 中西卓也, 澤村直哉, 朝日透, 逢坂哲彌

    Chemical Sensors 

    Presentation date: 2013.03

  • 有機ゲルマニウムGe‐132の投与による酸化ストレス抑制作用

    和田丈慶, 岩本久乃, 朝日透, 澤村直哉

    日本薬学会年会要旨集(CD-ROM) 

    Presentation date: 2013.03

  • 各種酸化ストレスに対するサリドマイドの神経細胞死抑制効果の解析

    大平浩史, 山田春佳, 朝日透, 澤村直哉

    日本生化学会大会(Web) 

    Presentation date: 2012.12

  • デルタロドプシンのミトコンドリア特異的発現:パーキンソン病治療への応用

    和田丈慶, 原清敬, 朝日透, 澤村直哉

    日本生化学会大会(Web) 

    Presentation date: 2012.12

  • CereblonはそのE3 ubiquitin ligase活性を介してaggresomeに局在する(Cereblon localizes at aggresomes through its E3 ubiquitin ligase activity)

    若林 慧, 山田 春佳, 朝日 透, 澤村 直哉

    日本生化学会大会プログラム・講演要旨集 

    Presentation date: 2012.12

  • サリドマイドとそのエナンチオマーによる神経保護作用の分子メカニズム

    山田春佳, 大平浩史, 若林慧, 朝日透, 澤村直哉

    日本薬学会年会要旨集 

    Presentation date: 2012.03

  • Aβ凝集時の足場としてのCHRNA7の役割

    キョウ 曄, 和田 丈慶, 朝日 透, 澤村 直哉

    日本薬学会年会要旨集 

    Presentation date: 2012.03

  • ポリL‐及びDL‐乳酸ナノシートの微細構造解析

    宇田川瑛弘, 大森衣里子, 川本裕子, 澤村直哉, 武岡真司, 朝日透

    応用物理学関係連合講演会講演予稿集(CD-ROM) 

    Presentation date: 2012.02

  • Aβ凝集時の足場としてのCHRNA7タンパクの役割(CHRNA7 as scaffold molecule for Aβ aggregation)

    きょ 曄, 和田 丈慶, 朝日 透, 澤村 直哉

    神経化学 

    Presentation date: 2011.09

  • 酸化ストレスに対するサリドマイドとそのエナンチオマーによる神経保護作用(Neuroprotective effect of thalidomide and its enantiomers against oxidative stress)

    山田 春佳, 大平 浩史, 朝日 透, 澤村 直哉

    神経化学 

    Presentation date: 2011.09

  • 高異方性コラーゲンシートの光学的性質

    中川鉄馬, 荻野禎之, 鈴木俊哉, 田中真人, 田中佑治, 大和雅之, 松尾光一, 澤村直哉, 朝日透

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2011.05

  • サリドマイドのエナンチオ選択的な神経細胞死抑制効果

    澤村直哉, 山田春佳, 朝日透

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2011.05

  • ポリL‐乳酸及びポリDL‐乳酸ナノシートの微細構造解析

    宇田川瑛弘, 大森衣里子, 石川和彦, 鈴木俊哉, 澤村直哉, 武岡真司, 朝日透

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2011.05

  • 培養哺乳類細胞における古細菌ロドプシンのミトコンドリア特異的発現(MITOCHONDRIA-SPECIFIC EXPRESSION OF ARCHAEBACTERIAL RHODOPSIN IN CULTURED MAMMALIAN CELLS)

    和田 丈慶, 原 清敬, 朝日 透, 澤村 直哉

    日本細胞生物学会大会講演要旨集 

    Presentation date: 2011.05

  • 神経保護におけるサリドマイドのエナンチオ特異的な影響(The enantiospecific effect of thalidomide in neuroprotection)

    山田 春佳, 朝日 透, 澤村 直哉

    日本細胞生物学会大会講演要旨集 

    Presentation date: 2011.05

  • ポリ(L)乳酸からなるナノシートの微細構造と機能の関係

    大森衣里子, 藤枝俊宣, 澤村直哉, 武岡真司, 朝日透

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2010.07

  • サリドマイドとそのエナンチオマーによる神経保護作用の解析

    澤村直哉, 山田春佳, 朝日透

    シンポジウム「モレキュラー・キラリティー」講演要旨集 

    Presentation date: 2010.07

  • スフィンゴ脂質によるアミロイド前駆体蛋白の代謝制御

    澤村 直哉, 高 美姫, 于 文新, ゾウ・クン, 花田 賢太郎, 鈴木 利治, きょう 建生, 柳澤 勝彦, 道川 誠

    Dementia Japan 

    Presentation date: 2004.08

  • アミロイドbeta-蛋白(Abeta)1-42による神経毒性に対するAbeta1-40の細胞保護作用の検討(Amyloid beta-Protein (Abeta) 1-40 Protects Neurons from Damage Induced by Abeta1-42 in Culture and in Rat Brain)

    Zou Kun, Kim Daesung, 垣尾 敦子, Byun Kyunghee, Gong Jian-Sheng, Kim Myeongju, 澤村 直哉, 西本 清一, 松崎 勝巳, Lee Bonghee, 柳澤 勝彦, 道川 誠

    神経化学 

    Presentation date: 2003.08

  • Aβ1-42によって誘導される神経毒性に対するAβ1-40の細胞保護作用の検討

    Zou Kun, Kim Daesung, Byun Kyunghee, Gong Jian-Sheng, Kim Myeongju, 澤村 直哉, Lee Bonghee, 柳澤 勝彦, 道川 誠

    Dementia Japan 

    Presentation date: 2003.08

  • ニーマンピック病C型モデル細胞におけるタウ蛋白のリン酸化の検討

    澤村 直哉, きょう 建生, Chang Ta-Yuan, 柳澤 勝彦, 道川 誠

    Dementia Japan 

    Presentation date: 2002.08

  • ヒトアポリポ蛋白E3-,E4-ノックインマウスから調整したアストロサイトにおけるアイソフォーム依存的コレステロール搬出機構の検討

    きょう 建生, 小林 まり子, 林 秀樹, 鄒 鶤, 澤村 直哉, 藤田 忍, 柳澤 勝彦, 道川 誠

    Dementia Japan 

    Presentation date: 2002.08

  • ニーマンピック病C型モデルマウスにおけるMAPKの活性化に伴うタウ蛋白の部位特異的なリン酸化

    澤村 直哉, きょう 建生, 二宮 治明, 大野 耕策, 柳澤 勝彦, 道川 誠

    Dementia Japan 

    Presentation date: 2001.08

  • 細胞内コレステロール量依存的タウ蛋白リン酸化調節の検討

    道川 誠, 范 企文, 澤村 直哉, 愈 い, 千田 隆夫, 柳澤 勝彦

    神経化学 

    Presentation date: 2000.10

  • ニーマンピック病C型モデルマウスにおけるタウ蛋白のリン酸化の検討

    澤村 直哉, きょう 建生, 柳澤 勝彦, 道川 誠

    神経化学 

    Presentation date: 2000.10

  • 凝集したAmyloid β-proteinは神経細胞におけるコレステロール代謝に大きな影響を及ぼす

    きょう 建生, 澤村 直哉, 范 企文, 柳澤 勝彦, 道川 誠

    神経化学 

    Presentation date: 2000.10

  • 変異型presenilin 2トランスジェニックマウス脳内低密度膜ドメインにおけるAβ42の蓄積

    澤村 直哉, 小山 文隆, 森島 真帆, 井原 康夫

    神経化学 

    Presentation date: 1999.09

  • 変異型presenilin2トランスジェニックマウス脳内での加齢に伴うAβ42産生の増加

    澤村 直哉, 小山 文隆, 小林 喜美男, 森島 真帆, 倉持 隆司, 伊藤 守, 富田 泰輔, 丸山 敬, 西道 隆臣, 岩坪 威

    Dementia Japan 

    Presentation date: 1998.09

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