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γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production

γ-Secretase cleaves the carboxyl-terminal fragment (βCTF) of APP not only in the middle of the transmembrane domain (γ-cleavage), but also at sites close to the membrane/cytoplasm boundary (ε-cleavage), to produce the amyloid β protein (Aβ) and the APP intracellular domain (AICD), respectively. The...

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Autores principales: Takami, Mako, Funamoto, Satoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549393/
https://www.ncbi.nlm.nih.gov/pubmed/23346458
http://dx.doi.org/10.1155/2012/591392
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author Takami, Mako
Funamoto, Satoru
author_facet Takami, Mako
Funamoto, Satoru
author_sort Takami, Mako
collection PubMed
description γ-Secretase cleaves the carboxyl-terminal fragment (βCTF) of APP not only in the middle of the transmembrane domain (γ-cleavage), but also at sites close to the membrane/cytoplasm boundary (ε-cleavage), to produce the amyloid β protein (Aβ) and the APP intracellular domain (AICD), respectively. The AICD49–99 and AICD50–99 species were identified as counterparts of the long Aβ species Aβ48 and Aβ49, respectively. We found that Aβ40 and AICD50–99 were the predominant species in cells expressing wild-type APP and presenilin, whereas the production of Aβ42 and AICD49–99 was enhanced in cells expressing familial Alzheimer's disease mutants of APP and presenilin. These long Aβ species were identified in cell lysates and mouse brain extracts, which suggests that ε-cleavage is the first cleavage of βCTF to produce Aβ by γ-secretase. Here, we review the progress of research on the mechanism underlying the proteolysis of the APP transmembrane domain based on tri- and tetrapeptide release.
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spelling pubmed-35493932013-01-23 γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production Takami, Mako Funamoto, Satoru Int J Alzheimers Dis Review Article γ-Secretase cleaves the carboxyl-terminal fragment (βCTF) of APP not only in the middle of the transmembrane domain (γ-cleavage), but also at sites close to the membrane/cytoplasm boundary (ε-cleavage), to produce the amyloid β protein (Aβ) and the APP intracellular domain (AICD), respectively. The AICD49–99 and AICD50–99 species were identified as counterparts of the long Aβ species Aβ48 and Aβ49, respectively. We found that Aβ40 and AICD50–99 were the predominant species in cells expressing wild-type APP and presenilin, whereas the production of Aβ42 and AICD49–99 was enhanced in cells expressing familial Alzheimer's disease mutants of APP and presenilin. These long Aβ species were identified in cell lysates and mouse brain extracts, which suggests that ε-cleavage is the first cleavage of βCTF to produce Aβ by γ-secretase. Here, we review the progress of research on the mechanism underlying the proteolysis of the APP transmembrane domain based on tri- and tetrapeptide release. Hindawi Publishing Corporation 2012 2012-12-31 /pmc/articles/PMC3549393/ /pubmed/23346458 http://dx.doi.org/10.1155/2012/591392 Text en Copyright © 2012 M. Takami and S. Funamoto. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Article
Takami, Mako
Funamoto, Satoru
γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title_full γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title_fullStr γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title_full_unstemmed γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title_short γ-Secretase-Dependent Proteolysis of Transmembrane Domain of Amyloid Precursor Protein: Successive Tri- and Tetrapeptide Release in Amyloid β-Protein Production
title_sort γ-secretase-dependent proteolysis of transmembrane domain of amyloid precursor protein: successive tri- and tetrapeptide release in amyloid β-protein production
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3549393/
https://www.ncbi.nlm.nih.gov/pubmed/23346458
http://dx.doi.org/10.1155/2012/591392
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