WeightNameValue
1000 Titel
  • Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization
1000 Autor/in
  1. Richter, Luise |
  2. Munter, Lisa-Marie |
  3. Ness, Julia |
  4. Hildebrand, Peter W. |
  5. Dasari, Muralidhar |
  6. Unterreitmeier, Stephanie |
  7. Bulic, Bruno |
  8. Beyermann, Michael |
  9. Gust, Ronald |
  10. Reif, Bernd |
  11. Weggen, Sascha |
  12. Langosch, Dieter |
  13. Multhaup, Gerd |
1000 Erscheinungsjahr 2010
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2010-08-17
1000 Erschienen in
1000 Quellenangabe
  • 107(33): 14597–14602
1000 FRL-Sammlung
1000 Verlagsversion
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930477/ |
  • http://doi.org/10.1073/pnas.1003026107 |
1000 Ergänzendes Material
  • http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1003026107/-/DCSupplemental |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by γ-secretase result in the release of amyloid-β (Aβ) peptides of variable length. Aβ peptides with 42 amino acids appear to be the key pathogenic species in Alzheimer’s disease, as they are believed to initiate neuronal degeneration. Sulindac sulfide, which is known as a potent γ-secretase modulator (GSM), selectively reduces Aβ42 production in favor of shorter Aβ species, such as Aβ38. By studying APP–TMS dimerization we previously showed that an attenuated interaction similarly decreased Aβ42 levels and concomitantly increased Aβ38 levels. However, the precise molecular mechanism by which GSMs modulate Aβ production is still unclear. In this study, using a reporter gene-based dimerization assay, we found that APP–TMS dimers are destabilized by sulindac sulfide and related Aβ42-lowering compounds in a concentration-dependent manner. By surface plasmon resonance analysis and NMR spectroscopy, we show that sulindac sulfide and novel sulindac-derived compounds directly bind to the Aβ sequence. Strikingly, the attenuated APP–TMS interaction by GSMs correlated strongly with Aβ42-lowering activity and binding strength to the Aβ sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP–TMS. We conclude that these GSMs decrease Aβ42 levels by modulating APP–TMS interactions. This effect specifically emphasizes the importance of the dimeric APP–TMS as a promising drug target in Alzheimer’s disease.
1000 Fachgruppe
  1. Biologie |
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/creator/UmljaHRlciwgTHVpc2U=|https://frl.publisso.de/adhoc/creator/TXVudGVyLCBMaXNhLU1hcmll|https://frl.publisso.de/adhoc/creator/TmVzcywgSnVsaWE=|https://frl.publisso.de/adhoc/creator/SGlsZGVicmFuZCwgUGV0ZXIgVy4=|https://frl.publisso.de/adhoc/creator/RGFzYXJpLCBNdXJhbGlkaGFy|https://frl.publisso.de/adhoc/creator/VW50ZXJyZWl0bWVpZXIsIFN0ZXBoYW5pZQ==|https://frl.publisso.de/adhoc/creator/QnVsaWMsIEJydW5v|https://frl.publisso.de/adhoc/creator/QmV5ZXJtYW5uLCBNaWNoYWVs|https://frl.publisso.de/adhoc/creator/R3VzdCwgUm9uYWxk|http://orcid.org/0000-0001-7368-7198|https://frl.publisso.de/adhoc/creator/V2VnZ2VuLCBTYXNjaGE=|https://frl.publisso.de/adhoc/creator/TGFuZ29zY2gsIERpZXRlcg==|https://frl.publisso.de/adhoc/creator/TXVsdGhhdXAsIEdlcmQ=
1000 (Academic) Editor
1000 Förderer
  1. German Federal Ministry of Education and Research - Kompetenznetz Degenerative Demenzen |
  2. Alzheimer Forschung Initiative e.V |
  3. Deutsche Forschungsgemeinschaft |
  4. Hans und Ilse Breuer Stiftung |
1000 Fördernummer
  1. 01 GI 0723; 01 GI 0718; 01 GI 0926
  2. -
  3. MU901; SFB740; HI 1502/1-1
  4. -
1000 Förderprogramm
  1. -
  2. -
  3. -
  4. -
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer German Federal Ministry of Education and Research - Kompetenznetz Degenerative Demenzen |
    1000 Förderprogramm -
    1000 Fördernummer 01 GI 0723; 01 GI 0718; 01 GI 0926
  2. 1000 joinedFunding-child
    1000 Förderer Alzheimer Forschung Initiative e.V |
    1000 Förderprogramm -
    1000 Fördernummer -
  3. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer MU901; SFB740; HI 1502/1-1
  4. 1000 joinedFunding-child
    1000 Förderer Hans und Ilse Breuer Stiftung |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6402736.rdf
1000 Erstellt am 2017-06-02T08:34:58.321+0200
1000 Erstellt von 25
1000 beschreibt frl:6402736
1000 Bearbeitet von 218
1000 Zuletzt bearbeitet Mon Apr 30 13:49:14 CEST 2018
1000 Objekt bearb. Mon Apr 30 13:49:13 CEST 2018
1000 Vgl. frl:6402736
1000 Oai Id
  1. oai:frl.publisso.de:frl:6402736 |
1000 Sichtbarkeit Metadaten public
1000 Sichtbarkeit Daten public
1000 Gegenstand von

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