Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
Identifieur interne : 000F27 ( Pmc/Curation ); précédent : 000F26; suivant : 000F28Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse
Auteurs : Ayumi Takamura [Japon] ; Yasuhide Okamoto [Japon] ; Takeshi Kawarabayashi [Japon] ; Tatsuki Yokoseki [Japon] ; Masao Shibata [Japon] ; Akihiko Mouri [Japon] ; Toshitaka Nabeshima [Japon] ; Hui Sun [Japon] ; Koji Abe [Japon] ; Tsuneo Urisu [Japon] ; Naoki Yamamoto [Japon] ; Mikio Shoji [Japon] ; Katsuhiko Yanagisawa [Japon] ; Makoto Michikawa [Japon] ; Etsuro Matsubara [Japon]Source :
- Molecular Neurodegeneration [ 1750-1326 ] ; 2011.
Abstract
Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.
To specifically target toxic AβOs
Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.
Url:
DOI: 10.1186/1750-1326-6-20
PubMed: 21375782
PubMed Central: 3061944
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<author><name sortKey="Nabeshima, Toshitaka" sort="Nabeshima, Toshitaka" uniqKey="Nabeshima T" first="Toshitaka" last="Nabeshima">Toshitaka Nabeshima</name>
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<author><name sortKey="Yamamoto, Naoki" sort="Yamamoto, Naoki" uniqKey="Yamamoto N" first="Naoki" last="Yamamoto">Naoki Yamamoto</name>
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<author><name sortKey="Nabeshima, Toshitaka" sort="Nabeshima, Toshitaka" uniqKey="Nabeshima T" first="Toshitaka" last="Nabeshima">Toshitaka Nabeshima</name>
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<author><name sortKey="Sun, Hui" sort="Sun, Hui" uniqKey="Sun H" first="Hui" last="Sun">Hui Sun</name>
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<wicri:regionArea>Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi</wicri:regionArea>
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<author><name sortKey="Abe, Koji" sort="Abe, Koji" uniqKey="Abe K" first="Koji" last="Abe">Koji Abe</name>
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<author><name sortKey="Urisu, Tsuneo" sort="Urisu, Tsuneo" uniqKey="Urisu T" first="Tsuneo" last="Urisu">Tsuneo Urisu</name>
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<author><name sortKey="Yamamoto, Naoki" sort="Yamamoto, Naoki" uniqKey="Yamamoto N" first="Naoki" last="Yamamoto">Naoki Yamamoto</name>
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<country xml:lang="fr">Japon</country>
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<author><name sortKey="Shoji, Mikio" sort="Shoji, Mikio" uniqKey="Shoji M" first="Mikio" last="Shoji">Mikio Shoji</name>
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<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori</wicri:regionArea>
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<author><name sortKey="Yanagisawa, Katsuhiko" sort="Yanagisawa, Katsuhiko" uniqKey="Yanagisawa K" first="Katsuhiko" last="Yanagisawa">Katsuhiko Yanagisawa</name>
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<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi</wicri:regionArea>
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<author><name sortKey="Michikawa, Makoto" sort="Michikawa, Makoto" uniqKey="Michikawa M" first="Makoto" last="Michikawa">Makoto Michikawa</name>
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<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi</wicri:regionArea>
</affiliation>
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<author><name sortKey="Matsubara, Etsuro" sort="Matsubara, Etsuro" uniqKey="Matsubara E" first="Etsuro" last="Matsubara">Etsuro Matsubara</name>
<affiliation wicri:level="1"><nlm:aff id="I1">Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi</wicri:regionArea>
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<affiliation wicri:level="1"><nlm:aff id="I2">Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan</nlm:aff>
<country xml:lang="fr">Japon</country>
<wicri:regionArea>Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori</wicri:regionArea>
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<series><title level="j">Molecular Neurodegeneration</title>
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<imprint><date when="2011">2011</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.</p>
</sec>
<sec><title>Results</title>
<p>To specifically target toxic AβOs <italic>in vivo</italic>
, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.</p>
</sec>
<sec><title>Conclusion</title>
<p>Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Neurodegener</journal-id>
<journal-title-group><journal-title>Molecular Neurodegeneration</journal-title>
</journal-title-group>
<issn pub-type="epub">1750-1326</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">21375782</article-id>
<article-id pub-id-type="pmc">3061944</article-id>
<article-id pub-id-type="publisher-id">1750-1326-6-20</article-id>
<article-id pub-id-type="doi">10.1186/1750-1326-6-20</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Extracellular and intraneuronal HMW-AbetaOs represent a molecular basis of memory loss in Alzheimer's disease model mouse</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="A1"><name><surname>Takamura</surname>
<given-names>Ayumi</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<xref ref-type="aff" rid="I2">2</xref>
<email>ayumi@cc.hirosaki-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A2"><name><surname>Okamoto </surname>
<given-names>Yasuhide</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<xref ref-type="aff" rid="I3">3</xref>
<email>y-okamoto@immunas.co.jp</email>
</contrib>
<contrib contrib-type="author" id="A3"><name><surname>Kawarabayashi</surname>
<given-names>Takeshi</given-names>
</name>
<xref ref-type="aff" rid="I2">2</xref>
<email>tkawara@cc.hirosaki-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A4"><name><surname>Yokoseki</surname>
<given-names>Tatsuki</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<email>t-yokoseki@immunas.co.jp</email>
</contrib>
<contrib contrib-type="author" id="A5"><name><surname>Shibata</surname>
<given-names>Masao</given-names>
</name>
<xref ref-type="aff" rid="I3">3</xref>
<email>shibata@inacatv.ne.jp</email>
</contrib>
<contrib contrib-type="author" id="A6"><name><surname>Mouri</surname>
<given-names>Akihiko</given-names>
</name>
<xref ref-type="aff" rid="I4">4</xref>
<email>amouri@ccmfs.meijo-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A7"><name><surname>Nabeshima</surname>
<given-names>Toshitaka</given-names>
</name>
<xref ref-type="aff" rid="I4">4</xref>
<email>tnabeshi@ccmfs.meijo-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A8"><name><surname>Sun</surname>
<given-names>Hui</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>sunhuidalian@gmail.com</email>
</contrib>
<contrib contrib-type="author" id="A9"><name><surname>Abe</surname>
<given-names>Koji</given-names>
</name>
<xref ref-type="aff" rid="I5">5</xref>
<email>abekabek@cc.okayama-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A10"><name><surname>Urisu</surname>
<given-names>Tsuneo</given-names>
</name>
<xref ref-type="aff" rid="I6">6</xref>
<email>urisu@ims.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A11"><name><surname>Yamamoto</surname>
<given-names>Naoki</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>naokisan@ph.ritsumei.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A12"><name><surname>Shoji</surname>
<given-names>Mikio</given-names>
</name>
<xref ref-type="aff" rid="I2">2</xref>
<email>mshoji@cc.hirosaki-u.ac.jp</email>
</contrib>
<contrib contrib-type="author" id="A13"><name><surname>Yanagisawa</surname>
<given-names>Katsuhiko</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>katuhiko@ncgg.go.jp</email>
</contrib>
<contrib contrib-type="author" id="A14"><name><surname>Michikawa</surname>
<given-names>Makoto</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<email>michi@ncgg.go.jp</email>
</contrib>
<contrib contrib-type="author" corresp="yes" id="A15"><name><surname>Matsubara</surname>
<given-names>Etsuro</given-names>
</name>
<xref ref-type="aff" rid="I1">1</xref>
<xref ref-type="aff" rid="I2">2</xref>
<email>etsuro@cc.hirosaki-u.ac.jp</email>
</contrib>
</contrib-group>
<aff id="I1"><label>1</label>
Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology, Aichi, Japan</aff>
<aff id="I2"><label>2</label>
Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Aomori, Japan</aff>
<aff id="I3"><label>3</label>
Immunas Pharma Incorporation, Kanagawa, Japan</aff>
<aff id="I4"><label>4</label>
Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Aichi, Japan</aff>
<aff id="I5"><label>5</label>
Department of Neurology, Okayama University School of Medicine, Okayama, Japan</aff>
<aff id="I6"><label>6</label>
Department of Life and Coordination-Complex Molecular Science, Institute for Molecular Science, Aichi, Japan</aff>
<pub-date pub-type="collection"><year>2011</year>
</pub-date>
<pub-date pub-type="epub"><day>6</day>
<month>3</month>
<year>2011</year>
</pub-date>
<volume>6</volume>
<fpage>20</fpage>
<lpage>20</lpage>
<history><date date-type="received"><day>13</day>
<month>8</month>
<year>2010</year>
</date>
<date date-type="accepted"><day>6</day>
<month>3</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>Copyright ©2011 Takamura et al; licensee BioMed Central Ltd.</copyright-statement>
<copyright-year>2011</copyright-year>
<copyright-holder>Takamura et al; licensee BioMed Central Ltd.</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.0"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<self-uri xlink:href="http://www.molecularneurodegeneration.com/content/6/1/20"></self-uri>
<abstract><sec><title>Background</title>
<p>Several lines of evidence indicate that memory loss represents a synaptic failure caused by soluble amyloid β (Aβ) oligomers. However, the pathological relevance of Aβ oligomers (AβOs) as the trigger of synaptic or neuronal degeneration, and the possible mechanism underlying the neurotoxic action of endogenous AβOs remain to be determined.</p>
</sec>
<sec><title>Results</title>
<p>To specifically target toxic AβOs <italic>in vivo</italic>
, monoclonal antibodies (1A9 and 2C3) specific to them were generated using a novel design method. 1A9 and 2C3 specifically recognize soluble AβOs larger than 35-mers and pentamers on Blue native polyacrylamide gel electrophoresis, respectively. Biophysical and structural analysis by atomic force microscopy (AFM) revealed that neurotoxic 1A9 and 2C3 oligomeric conformers displayed non-fibrilar, relatively spherical structure. Of note, such AβOs were taken up by neuroblastoma (SH-SY5Y) cell, resulted in neuronal death. In humans, immunohistochemical analysis employing 1A9 or 2C3 revealed that 1A9 and 2C3 stain intraneuronal granules accumulated in the perikaryon of pyramidal neurons and some diffuse plaques. Fluoro Jade-B binding assay also revealed 1A9- or 2C3-stained neurons, indicating their impending degeneration. In a long-term low-dose prophylactic trial using active 1A9 or 2C3 antibody, we found that passive immunization protected a mouse model of Alzheimer's disease (AD) from memory deficits, synaptic degeneration, promotion of intraneuronal AβOs, and neuronal degeneration. Because the primary antitoxic action of 1A9 and 2C3 occurs outside neurons, our results suggest that extracellular AβOs initiate the AD toxic process and intraneuronal AβOs may worsen neuronal degeneration and memory loss.</p>
</sec>
<sec><title>Conclusion</title>
<p>Now, we have evidence that HMW-AβOs are among the earliest manifestation of the AD toxic process in mice and humans. We are certain that our studies move us closer to our goal of finding a therapeutic target and/or confirming the relevance of our therapeutic strategy.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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