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Mechanism for anti-AD effect of approved medicines

Research Project

Project/Area Number 24659037
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionKeio University

Principal Investigator

MIZUSHIMA Tohru  慶應義塾大学, 薬学部, 教授 (00264060)

Project Period (FY) 2012-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsアルツハイマー病
Research Abstract

Transforming growth factor (TGF)-B1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of AB, AB plaque deposition and synaptic loss. The treatment also up-regulated the expression of an AB-degrading enzyme and TGF-B1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. A single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when AB was concomitantly injected directly into the hippocampus.

Report

(3 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • Research Products

    (27 results)

All 2014 2013 2012 Other

All Journal Article (27 results) (of which Peer Reviewed: 11 results)

  • [Journal Article] Diclofenac protects cultured human corneal epithelial cells against hyperosmolarity and ameliorates corneal surface damage in a rat model of dry eye2014

    • Author(s)
      Sawazaki, R., Ishihara, T., Usui, S., Hayashi, E., Tahara, K., Hoshino, T., Higuchi, A., Nakamura, S., Tsubota, K. and Mizushima, T.
    • Journal Title

      Invest. Ophthalmol. Vis. Sci.

      Volume: 55 Pages: 2547-2556

    • Related Report
      2013 Final Research Report
  • [Journal Article] Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease2014

    • Author(s)
      Tanaka, K., Kurotsu, S., Asano, T., Yamakawa, N., Kobayashi D., Yamashita, Y., Yamazaki, H., Ishihara, T., Watanabe, H., Maruyama, T., Suzuki, H. and Mizushima, T.
    • Journal Title

      Sci. Rep.

      Volume: 28 Pages: 4510-4510

    • Related Report
      2013 Final Research Report
  • [Journal Article] Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity2014

    • Author(s)
      Yamakawa, N., Suzuki, K., Yamashita, Y., Katsu, T., Hanaya, K., Shoji, M., Sugai, T. and Mizushima, T.
    • Journal Title

      Bioorg. & Medic. Chem.

      Volume: 22 Issue: 8 Pages: 2529-2534

    • DOI

      10.1016/j.bmc.2014.02.032

    • Related Report
      2013 Final Research Report
  • [Journal Article] Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease2013

    • Author(s)
      Tanaka, K., Ishihara, T., Sugizaki, T., Kobayashi D., Yamashita, Y., Tahara, K., Yamakawa, N., Iijima, K., Mogushi, K., Tanaka, H., Sato, K., Suzuki, H. and Mizushima, T.
    • Journal Title

      Nature Communications

      Volume: 4 Pages: 2686-2686

    • Related Report
      2013 Final Research Report
  • [Journal Article] Suppression of Alzheimer's disease-related phenotypes by geranygeranylacetone in mice2013

    • Author(s)
      Hoshino, T., Suzuki, K., Matsushima, T., Yamakawa, N., Suzuki, T. and Mizushima, T
    • Journal Title

      PLoS One

      Volume: 8 Issue: 10 Pages: e76306-e76306

    • DOI

      10.1371/journal.pone.0076306

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Chemo-enzymatic enantioconvergent approach toward ethyl shikimate from ethyl 5-hydroxy-3,4-isopropylidenedioxycycloh ex-1-enecarboxylate2013

    • Author(s)
      Yamashita, Y., Hanaya, K., Sugai, T., Mizushima, T. and Shoji, M.
    • Journal Title

      Tetrahedron

      Volume: 69 Pages: 6527-6532

    • Related Report
      2013 Final Research Report
  • [Journal Article] Prostaglandin E1-encapsulated nanoparticles improve walking activity in an experimental rat model of intermittent claudication2013

    • Author(s)
      Ishihara, T., Yamashita, Y., Takasaki, N., Yamamoto, S., Hayashi, E., Tahara, K., Takenaga, M., Yamakawa, N., Ishihara, T., Kasahara, T. and Mizushima, T.
    • Journal Title

      J. Pharm. Pharmacol.

      Volume: 65 Pages: 1187-1194

    • Related Report
      2013 Final Research Report
  • [Journal Article] Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression.2013

    • Author(s)
      Tanaka R, Watanabe H, Kodama A, Chuang VT, Ishima Y, Hamasaki K, Tanaka K, Mizushima T, Otagiri M, Maruyama T.
    • Journal Title

      J Pharmacol Exp Ther.

      Volume: 345 Issue: 2 Pages: 271-283

    • DOI

      10.1124/jpet.112.201814

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen2013

    • Author(s)
      Yamakawa, N., Suemasu, S., Watanabe, H., Tahara, K., Tanaka, K., Okamoto, Y., Ohtsuka, M., Maruyama, T. and Mizushima, T.
    • Journal Title

      Drug Metab. Pharmacokinet

      Volume: 28 Pages: 118-124

    • NAID

      130004933526

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Journal Article] Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice2013

    • Author(s)
      Matsuda, M., Hoshino, T., Yamakawa, N., Tahara, K., Adachi, H., Sobue, G., Maji, D., Ihn, H. and Mizushima, T.
    • Journal Title

      J. Invest. Dermatol.

      Volume: 113 Issue: 4 Pages: 19-28

    • DOI

      10.1038/jid.2012.383

    • Related Report
      2013 Final Research Report
  • [Journal Article] Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide synthase inhibitors.2013

    • Author(s)
      Manabu Nakashita
    • Journal Title

      Dig. Dis. Sci.

      Volume: 58 Pages: 354-62

    • DOI

      10.1007/s10620-012-2350-x

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice.2013

    • Author(s)
      Hoshino, T., Suzuki, K., Matsushima, T., Yamakawa, N., Suzuki, T. and Mizushima, T.
    • Journal Title

      PLoS One

      Volume: 8 Issue: 10 Pages: e76303-e76303

    • DOI

      10.1371/journal.pone.0076303

    • NAID

      120005365906

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease.2013

    • Author(s)
      Tanaka, K., Ishihara, T., Sugizaki, T., Kobayashi D., Yamashita, Y., Tahara, K., Yamakawa, N., Iijima, K., Mogushi, K., Tanaka, H., Sato, K., Suzuki, H. and Mizushima, T.
    • Journal Title

      Nature Communications

      Volume: 4 Pages: 2686-2686

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression of 150-kDa oxygen-regulated protein (QRP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice2012

    • Author(s)
      Tanaka, K., et al.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 425 Issue: 4 Pages: 818-824

    • DOI

      10.1016/j.bbrc.2012.07.158

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Identification of a unique nsaid, fluoro-loxoprofen with gastroprotective activity.2012

    • Author(s)
      Suemasu S., et al.
    • Journal Title

      Biochem Pharmacol.

      Volume: 84 Issue: 11 Pages: 1470-1481

    • DOI

      10.1016/j.bcp.2012.09.016

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Effects of lecithinized superoxide dismutase and/or pirfenidone against bleomycin-induced pulmonary fibrosis2012

    • Author(s)
      Tanaka, K., Azuma, A., Miyazaki, Y., Sato, K. and Mizushima, T.
    • Journal Title

      Chest

      Volume: 142 Pages: 1011-1019

    • Related Report
      2013 Final Research Report
  • [Journal Article] Development of NSAIDs with lower gastric side effect2012

    • Author(s)
      Mizushima, T
    • Journal Title

      Frontier of Gastrointestinal Research

      Volume: 30 Pages: 71-78

    • DOI

      10.1159/000338396

    • ISBN
      9783318021837, 9783318021844
    • Related Report
      2013 Final Research Report
  • [Journal Article] Synthesis and biological evaluation of derivatives of 2-{2-fluoro-4-[(2-oxocyclopentyl)methyl ]phenyl}propanoic acid : Non-steroidal anti-inflammatory drugs with low gastric ulcerogenic activity2012

    • Author(s)
      Yamakawa, N., Suemasu, S., Okamoto, Y., Tanaka, K., Ishihara, T., Asano, T., Miyata, k., Ohtsuka, M. and Mizushima, T.
    • Journal Title

      J. Med. Chem.

      Volume: 55 Pages: 5143-5150

    • Related Report
      2013 Final Research Report
  • [Journal Article] Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice2012

    • Author(s)
      Tanaka, K., Sato, K., Aoshiba, K., Azuma, A. and Mizushima, T.
    • Journal Title

      Am. J. Physiol. Lung Cell. Mol. Physiol.

      Volume: 302 Issue: 12 Pages: L1250-L1261

    • DOI

      10.1152/ajplung.00019.2012

    • Related Report
      2013 Final Research Report
  • [Journal Article] Effects of β-(1,3-1,6)-D-glucan on irritable bowel syndrome-related colonic hypersensitivity2012

    • Author(s)
      Asano, T., Suzuki, H., et al
    • Journal Title

      Biochem.Biophys.Res.Com.

      Volume: 420(2) Issue: 2 Pages: 444-449

    • DOI

      10.1016/j.bbrc.2012.03.015

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] purification and characterization of hsp-inducers from eupatorium lindleyanum2012

    • Author(s)
      Yamashita, Y., Ikeda, T., Matsuda, M., Maji, D., Hoshino, T. and Mizushima, T.
    • Journal Title

      Biochem. Pharmacol.

      Volume: 82 Pages: 909-922

    • Related Report
      2013 Final Research Report
  • [Journal Article] Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP_4 receptor2012

    • Author(s)
      Hoshino, T., Namba, T., Takehara, M., Murao, N., Sugimoto, Y., Narumiya, S., Matsushima, T., Suzuki, T. and Mizushima, T.
    • Journal Title

      J. Neurochem.

      Volume: 120 Pages: 795-805

    • Related Report
      2013 Final Research Report
  • [Journal Article] Improvement of cognitive function in Alzheimer’s disease model mice by genetic and pharmacological inhibition of the EP4 receptor.2012

    • Author(s)
      Hoshino.T.et al.
    • Journal Title

      J. Neurochem.

      Volume: 120 Pages: 795-805

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Purification and characterization of hsp-inducers from eupatorium lindleyanum.2012

    • Author(s)
      Yamashita. Y. et al.
    • Journal Title

      Biochem. Pharmacol.

      Volume: 82 Pages: 909-922

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Effects of β-(1,3-1,6)-D-glucan on irritable bowel syndrome-related colonic hypersensitivity.2012

    • Author(s)
      Asano.T. et al.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 420 Pages: 444-449

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities

    • Author(s)
      Yamashita, Y., Tanaka, K., Asano, T., Yamakawa, N., Kobayashi D., Ishihara, T., Hanaya, K., Shoji, M., Sugai, T., Wada, M., Mashimo, T., Fukunishi, Y. and Mizushima, T.
    • Journal Title

      Bioorg. & Medic. Chem.

      Volume: (in press)

    • Related Report
      2013 Final Research Report
  • [Journal Article] Ameliorative effect of mepenzolate bromide against pulmonary fibrosis

    • Author(s)
      Kurotsu, S., Tanaka, K., Niino, T., Sugizaki, T., Azuma, A., Suzuki, H. and Mizushima, T.
    • Journal Title

      J. Pharmacol. Exp. Ther.

      Volume: (in press)

    • Related Report
      2013 Final Research Report

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Published: 2013-05-31   Modified: 2019-07-29  

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