@article{Mitterreiter2010-06-30Bepri-12547,
  year={2010},
  doi={10.1523/JNEUROSCI.1199-10.2010},
  title={Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms},
  number={26},
  volume={30},
  issn={0270-6474},
  journal={Journal of Neuroscience},
  pages={8974--8983},
  author={Mitterreiter, Stefan and Page, Richard M. and Kamp, Frits and Hopson, Jessika and Winkler, Edith and Ha, Huy-Riem and Hamid, Runa and Herms, Jochen and Mayer, Thomas U. and Nelson, Deborah J. and Steiner, Harald and Stahl, Tobias and Zeitschel, Ulrike and Rossner, Steffen and Haass, Christian and Lichtenthaler, Stefan F.}
}

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    <dc:contributor>Hamid, Runa</dc:contributor>
    <dc:creator>Zeitschel, Ulrike</dc:creator>
    <dc:creator>Hamid, Runa</dc:creator>
    <dc:creator>Mayer, Thomas U.</dc:creator>
    <dc:creator>Kamp, Frits</dc:creator>
    <dc:contributor>Zeitschel, Ulrike</dc:contributor>
    <dc:creator>Ha, Huy-Riem</dc:creator>
    <dc:creator>Page, Richard M.</dc:creator>
    <dc:contributor>Winkler, Edith</dc:contributor>
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    <dc:contributor>Stahl, Tobias</dc:contributor>
    <dc:creator>Winkler, Edith</dc:creator>
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    <dc:contributor>Kamp, Frits</dc:contributor>
    <dc:creator>Steiner, Harald</dc:creator>
    <dc:contributor>Steiner, Harald</dc:contributor>
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    <dc:creator>Nelson, Deborah J.</dc:creator>
    <dc:contributor>Ha, Huy-Riem</dc:contributor>
    <dc:creator>Lichtenthaler, Stefan F.</dc:creator>
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    <dc:contributor>Haass, Christian</dc:contributor>
    <dc:contributor>Page, Richard M.</dc:contributor>
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    <dc:contributor>Lichtenthaler, Stefan F.</dc:contributor>
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    <dcterms:bibliographicCitation>First publ. in: Journal of Neuroscience 30 (2010), 26, pp. 8974-8983</dcterms:bibliographicCitation>
    <dc:contributor>Hopson, Jessika</dc:contributor>
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    <dc:contributor>Mayer, Thomas U.</dc:contributor>
    <dc:contributor>Herms, Jochen</dc:contributor>
    <dcterms:abstract xml:lang="eng">The two proteases beta-secretase and gamma-secretase generate the amyloid beta peptide and are drug targets for Alzheimer's disease. Here we tested the possibility of targeting the cellular environment of beta-secretase cleavage instead of the beta-secretase enzyme itself. beta-Secretase has an acidic pH optimum and cleaves the amyloid precursor protein in the acidic endosomes. We identified two drugs, bepridil and amiodarone, that are weak bases and are in clinical use as calcium antagonists. Independently of their calcium-blocking activity, both compounds mildly raised the membrane-proximal, endosomal pH and inhibited beta-secretase cleavage at therapeutically achievable concentrations in cultured cells, in primary neurons, and in vivo in guinea pigs. This shows that an alkalinization of the cellular environment could be a novel therapeutic strategy to inhibit beta-secretase. Surprisingly, bepridil and amiodarone also modulated gamma-secretase cleavage independently of endosomal alkalinization. Thus, both compounds act as dual modulators that simultaneously target beta- and gamma-secretase through distinct molecular mechanisms. In addition to Alzheimer's disease, compounds with dual properties may also be useful for drug development targeting other membrane proteins.</dcterms:abstract>
    <dc:creator>Stahl, Tobias</dc:creator>
    <dc:creator>Rossner, Steffen</dc:creator>
    <dc:contributor>Rossner, Steffen</dc:contributor>
    <dc:creator>Herms, Jochen</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2011-06-20T08:09:18Z</dc:date>
    <dc:creator>Hopson, Jessika</dc:creator>
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    <dc:contributor>Nelson, Deborah J.</dc:contributor>
    <dc:contributor>Mitterreiter, Stefan</dc:contributor>
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    <dcterms:issued>2010-06-30</dcterms:issued>
    <dcterms:title>Bepridil and amiodarone simultaneously target the Alzheimer's disease beta- and gamma-secretase via distinct mechanisms</dcterms:title>
    <dc:rights>terms-of-use</dc:rights>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/12547"/>
    <dc:creator>Haass, Christian</dc:creator>
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