Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization
| العنوان: | Amyloid beta 42 peptide (Aβ42)-lowering compounds directly bind to Aβ and interfere with amyloid precursor protein (APP) transmembrane dimerization |
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| المؤلفون: | Muralidhar Dasari, Julia Ness, Sascha Weggen, Bruno Bulic, Gerd Multhaup, Stephanie Unterreitmeier, Lisa-Marie Munter, Ronald Gust, Luise Richter, Peter W. Hildebrand, Bernd Reif, Dieter Langosch, Michael Beyermann |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America, 107(33): 14597–14602 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Models, Molecular, CHO Cells, Plasma protein binding, Amyloid beta-Protein Precursor, Cricetulus, Sulindac, Cricetinae, Amyloid precursor protein, Animals, Humans, Amino Acid Sequence, Peptide sequence, chemistry.chemical_classification, Amyloid beta-Peptides, Multidisciplinary, Molecular Structure, biology, Chemistry, P3 peptide, Surface Plasmon Resonance, Biological Sciences, Peptide Fragments, Transmembrane protein, Amino acid, Ectodomain, Biochemistry, biology.protein, Amyloid Precursor Protein Secretases, Protein Multimerization, Amyloid precursor protein secretase, Protein Binding |
| الوصف: | Following ectodomain shedding by beta-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of the amyloid precursor protein (APP) catalyzed by gamma-secretase result in the release of amyloid-beta (Abeta) peptides of variable length. Abeta 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 gamma-secretase modulator (GSM), selectively reduces Abeta42 production in favor of shorter Abeta species, such as Abeta38. By studying APP-TMS dimerization we previously showed that an attenuated interaction similarly decreased Abeta42 levels and concomitantly increased Abeta38 levels. However, the precise molecular mechanism by which GSMs modulate Abeta 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 Abeta42-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 Abeta sequence. Strikingly, the attenuated APP-TMS interaction by GSMs correlated strongly with Abeta42-lowering activity and binding strength to the Abeta sequence. Molecular docking analyses suggest that certain GSMs bind to the GxxxG dimerization motif in the APP-TMS. We conclude that these GSMs decrease Abeta42 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. |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ba34c6bfcfa929650b3f6e4b1809a369Test https://doi.org/10.1073/pnas.1003026107Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ba34c6bfcfa929650b3f6e4b1809a369 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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