ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons
| العنوان: | ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons |
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| المؤلفون: | Peer-Hendrik Kuhn, Huanhuan Wang, Elisabeth Kremmer, Steffen Roßner, Bastian Dislich, Stefan F. Lichtenthaler, Joachim W. Ellwart, Ulrike Zeitschel, Alessio Colombo |
| المصدر: | EMBO J. 29, 3020-3032 (2010) The EMBO journal 29(17), 3020-3032 (2010). doi:10.1038/emboj.2010.167 |
| بيانات النشر: | Nature Publ. Group, 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Proteases, ADAM10, Article, Mass Spectrometry, General Biochemistry, Genetics and Molecular Biology, Cell Line, ADAM10 Protein, Amyloid beta-Protein Precursor, Mice, Aplp1 protein, mouse, ddc:570, metabolism [Amyloid beta-Protein Precursor], Adam10 protein, mouse, mental disorders, Amyloid precursor protein, Animals, Humans, Molecular Biology, Neurons, enzymology [Neurons], General Immunology and Microbiology, biology, General Neuroscience, P3 peptide, ADAM, amyloid precursor protein, neuro-degeneration, proteases, alpha-secretase, NECROSIS-FACTOR-ALPHA, METALLOPROTEASE-DISINTEGRIN MDC9, ONSET ALZHEIMERS-DISEASE, BETA-SECRETASE, CONVERTING-ENZYME, HIPPOCAMPAL-NEURONS, CLEAVAGE, APP, ECTODOMAIN, PATHWAY, Membrane Proteins, ADAM Proteins, metabolism [Amyloid Precursor Protein Secretases], Biochemistry of Alzheimer's disease, Alpha secretase, Biochemistry, metabolism [Neurons], metabolism [ADAM Proteins], biology.protein, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase, metabolism [Membrane Proteins] |
| الوصف: | The amyloid precursor protein (APP) undergoes constitutive shedding by a protease activity called alpha-secretase. This is considered an important mechanism preventing the generation of the Alzheimer's disease amyloid-beta peptide (Abeta). alpha-Secretase appears to be a metalloprotease of the ADAM family, but its identity remains to be established. Using a novel alpha-secretase-cleavage site-specific antibody, we found that RNAi-mediated knockdown of ADAM10, but surprisingly not of ADAM9 or 17, completely suppressed APP alpha-secretase cleavage in different cell lines and in primary murine neurons. Other proteases were not able to compensate for this loss of alpha-cleavage. This finding was further confirmed by mass-spectrometric detection of APP-cleavage fragments. Surprisingly, in different cell lines, the reduction of alpha-secretase cleavage was not paralleled by a corresponding increase in the Abeta-generating beta-secretase cleavage, revealing that both proteases do not always compete for APP as a substrate. Instead, our data suggest a novel pathway for APP processing, in which ADAM10 can partially compete with gamma-secretase for the cleavage of a C-terminal APP fragment generated by beta-secretase. We conclude that ADAM10 is the physiologically relevant, constitutive alpha-secretase of APP. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::74366ab201c168b378ab9bae33bfa279Test https://push-zb.helmholtz-muenchen.de/frontdoor.php?source_opus=6013Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....74366ab201c168b378ab9bae33bfa279 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |