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2010 Fiscal Year Final Research Report

Neuronal death-inhibiting therapy for neurodegenerative disease

Research Project

  • PDF
Project/Area Number 20390072
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKeio University

Principal Investigator

MATSUOKA Masaaki  Keio University, 医学部, 主任教授 (70222297)

Project Period (FY) 2008 – 2010
Keywords神経変性疾患 / アルツハイマー病 / 筋萎縮性側索硬化症
Research Abstract

In this study, we have examined the neuronal death mechanism underlying Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). We also performed basic and translational research to search for endogenous neuroprotective factor Humanin.
1, The presenilin(PS)1/PS2 involvement of TGFβ2-induced neuronal death via APP. We found that PS1/PS2 are essential for TGFβ2-induced neuronal death via APP. MOCA is the key molecule that unifies APP-mediated death signal to PS-mediated death signal.
2. Identification of EH as an endogenous agonist of Humanin. We found that EH is a far more potent endogenous agonist of Humanin. EH, injected intracerebraventricularly or intraperitoneally, showed anti-AD-related dementia activity in vivo. A series of experiments also showed that EH, highly expressed in skin tissues, is transported across blood-brain barrier to the central nervous system. These results suggest that EH play a main role in inhibiting AD-related neuronal death and dysfunction in vivo as a physiological defense factor.
3. Fishing of small chemicals mimicking Humanin. We found that a couple of small chemicals induced the oligomerization of the Humanin receptor subunits. This result confirmed that they have Humanin activity.
4. Preclinical test of Colivelin, a potent Humanin derivative. We found that intranasally administered Colivelin was efficiently transported to the central nervous system without modification or cleavage.
5. The ALS pathogenesis. We clarified the detailed mechanism underlying P56SVAPB-induced ALS form the standpoint of unfolded protein response. We also found that low-grade overexpression of TDP-43 induces motor neuron death mediated by the upregulation of Bim and the downregulation of Bcl-xL. TDP-43-induced death is attenuated by its cleavage by activated caspases. We finally found that BTBD-10-deficient C. elegans showed death of touch neurons and motor abnormality.

  • Research Products

    (20 results)

All 2011 2010 2009 Other

All Journal Article (18 results) (of which Peer Reviewed: 17 results) Presentation (2 results)

  • [Journal Article] VSTM2L IS A NOVEL SECRETED ANTAGONIST OF THE NEUROPROTECTIVE PEPTIDE HUMANIN2011

    • Author(s)
      Lara Rossini, Hashimoto Y, Suzuki H, Kurita M, Marco Gianfriddo, Carla Scali, Renza Roncarati, Davide Franceschini, Giuseppe Pollio, Lorenza Trabalzin, Georg C. Terstappen, Matsuoka M, Caricasole A
    • Journal Title

      FASEB J. (in press)

    • Peer Reviewed
  • [Journal Article] TDP-43-induced death is associated with altered regulation of BIM and BCL-XL and attenuated by caspase-mediated TDP-43 cleavage.2011

    • Author(s)
      Suzuki H, Lee K, Matsuoka M
    • Journal Title

      J Biol Chem.(Epub ahead of print)

    • Peer Reviewed
  • [Journal Article] Humanin Signal for Alzheimer's Disease2011

    • Author(s)
      Matsuoka M
    • Journal Title

      J Alzheimers Dis.(Epub ahead of print)

    • Peer Reviewed
  • [Journal Article] Humanin and the receptors for humanin.

    • Author(s)
      Matsuoka M, Hashimoto Y
    • Journal Title

      Mol Neurobiol. 41

      Pages: 22-28

    • Peer Reviewed
  • [Journal Article] Immunolocalization of humanin in human sperm and testis.

    • Author(s)
      Moretti E, Giannerini V, Rossini L, Matsuoka M, Trabalzini L, Collodel G
    • Journal Title

      Fertil Steril.(Epub ahead of print)

  • [Journal Article] TAG-1 is an inhibitor of TGFbeta2-induced neuronal death via amyloid beta precursor protein.

    • Author(s)
      Tachi N, Hashimoto Y, Nawa M, Matsuoka M
    • Journal Title

      Biochem Biophys Res Commun. 394

      Pages: 119-125

    • Peer Reviewed
  • [Journal Article] Transforming growth factor beta2 level is elevated in nurons of Alzheimer's disease brain.

    • Author(s)
      Noguchi A, Nawa M, Aiso S, Okamoto K, Matsuoka M
    • Journal Title

      Int J.Neurosci. 120

      Pages: 168-175

    • Peer Reviewed
  • [Journal Article] Colivelin--drug therapy for patients with Alzheimer's disease.

    • Author(s)
      Matsuoka M
    • Journal Title

      Nippon Yakurigaku Zasshi. 135

      Pages: 263

    • Peer Reviewed
  • [Journal Article] Practical pharmacology training method for undergraduate medical students using a pharmacokinetic simulation model.

    • Author(s)
      Hara I, Matsuoka M
    • Journal Title

      Nippon Yakurigaku Zasshi. 136

      Pages: 155-159

    • Peer Reviewed
  • [Journal Article] Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alfa/WSX-1/gp130.

    • Author(s)
      Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M
    • Journal Title

      Mol.Biol.Cell 20

      Pages: 2864-2873

    • Peer Reviewed
  • [Journal Article] Identification of soluble WSX-1 not as a dominant-negative but as an alternative functional subunit of a eceptor for an anti-Alzheimer's disease rescue factor Humanin.

    • Author(s)
      Hashimoto Y, Kurita M, Matsuoka M
    • Journal Title

      Biochem Biophys Res Commun. 389

      Pages: 95-99

    • Peer Reviewed
  • [Journal Article] ALS-linked P56S-VAPB mutant predisposes motor neurons to ER stress-induced death by inducing detergent-insoluble aggregation of wild-type VAPB

    • Author(s)
      Suzuki H, Kanekura K, Levine T, Kohno K, Olkkonen V, Aiso S, Matsuoka M
    • Journal Title

      J Neurochem. 108

      Pages: 973-998

    • Peer Reviewed
  • [Journal Article] Amyloid-beta causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons.

    • Author(s)
      Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, Aiso S
    • Journal Title

      Mol Psychiatry. 14

      Pages: 206-222

    • Peer Reviewed
  • [Journal Article] HUMANIN ; A Defender against Alzheimer's disease.

    • Author(s)
      Matsuoka M
    • Journal Title

      Recent Patents in CNS Drug Discov. 4

      Pages: 37-42

    • Peer Reviewed
  • [Journal Article] ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.

    • Author(s)
      Kanekura K, Suzuki H, Aiso S, Matsuoka M
    • Journal Title

      Mol Neurobiol. 39

      Pages: 81-89

    • Peer Reviewed
  • [Journal Article] Anti-Apoptotic Action of Wnt5a in Dermal Fibroblasts Is Mediated by the PKA Signaling Pathway

    • Author(s)
      Torii K, Nishizawa K, Kawasaki A, Yamashita Y, Matsuoka M
    • Journal Title

      Cell Signal. 20

      Pages: 1256-1266

    • Peer Reviewed
  • [Journal Article] A novel Akt/PKB-interacting protein promotes cell adhesion and inhibits familial amyotrophic lateral sclerosis-linked mutant SOD1-induced neuronal death via inhibition of PP2A-mediated dephosphorylation of Akt/PKB.

    • Author(s)
      Nawa M. Kanekura K. Hashimoto Y. Aiso S. Matsuoka M.
    • Journal Title

      Cell Signal. 20

      Pages: 493-505

    • Peer Reviewed
  • [Journal Article] Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease.

    • Author(s)
      Yamada M, Chiba T, Sasabe J, Terashita K, Aiso S, Matsuoka M
    • Journal Title

      Neuropsychopharmacology 33

      Pages: 2020-2032

    • Peer Reviewed
  • [Presentation] TDP-43-induced death is associated with altered regulation of BIM and BCL-XL and attenuated by caspase-mediated TDP-43 cleavage.2010

    • Author(s)
      Suzuki H. Lee K. Matsuoka M.
    • Organizer
      The annual meeting of Society For Neuroscience
    • Place of Presentation
      San Diego
    • Year and Date
      20101113-20101117
  • [Presentation] Georg Christian Terstappen, and Andrea Caricasole VSTM2L is a novel secreted antagonist of the neuroprotective peptide humanin2009

    • Author(s)
      Lara Rossini, Hashimoto Y, Kurita M, Marco Gianfriddo, Carla Scali, Renza Roncarati, Davide Franceschini, Giuseppe Pollio, Lorenza Trabalzini, Matsuoka M
    • Organizer
      The annual meeting of Society For Neuroscience
    • Place of Presentation
      Chicago
    • Year and Date
      20091113-20091117

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Published: 2012-01-26   Modified: 2016-04-21  

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