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Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase

Amyloid β-protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease, the most common age-associated neurodegenerative disorder. Aβ is generated through intramembrane proteolysis of the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein (APP) by γ-secretase. Th...

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Autor principal: Morishima-Kawashima, Maho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245903/
https://www.ncbi.nlm.nih.gov/pubmed/25505888
http://dx.doi.org/10.3389/fphys.2014.00463
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author Morishima-Kawashima, Maho
author_facet Morishima-Kawashima, Maho
author_sort Morishima-Kawashima, Maho
collection PubMed
description Amyloid β-protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease, the most common age-associated neurodegenerative disorder. Aβ is generated through intramembrane proteolysis of the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein (APP) by γ-secretase. The initial cleavage by γ-secretase occurs in the membrane/cytoplasm boundary of the βCTF, liberating the APP intracellular domain (AICD). The remaining βCTFs, which are truncated at the C-terminus (longer Aβs), are then cropped sequentially in a stepwise manner, predominantly at three residue intervals, to generate Aβ. There are two major Aβ product lines which generate Aβ40 and Aβ42 with concomitant release of three and two tripeptides, respectively. Additionally, many alternative cleavages occur, releasing peptides with three to six residues. These modulate the Aβ product lines and define the species and quantity of Aβ generated. Here, we review our current understanding of the intramembrane cleavage of the βCTF by γ-secretase, which may contribute to the future goal of developing an efficient therapeutic strategy for Alzheimer's disease.
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spelling pubmed-42459032014-12-11 Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase Morishima-Kawashima, Maho Front Physiol Physiology Amyloid β-protein (Aβ) plays a central role in the pathogenesis of Alzheimer's disease, the most common age-associated neurodegenerative disorder. Aβ is generated through intramembrane proteolysis of the β-carboxyl terminal fragment (βCTF) of β-amyloid precursor protein (APP) by γ-secretase. The initial cleavage by γ-secretase occurs in the membrane/cytoplasm boundary of the βCTF, liberating the APP intracellular domain (AICD). The remaining βCTFs, which are truncated at the C-terminus (longer Aβs), are then cropped sequentially in a stepwise manner, predominantly at three residue intervals, to generate Aβ. There are two major Aβ product lines which generate Aβ40 and Aβ42 with concomitant release of three and two tripeptides, respectively. Additionally, many alternative cleavages occur, releasing peptides with three to six residues. These modulate the Aβ product lines and define the species and quantity of Aβ generated. Here, we review our current understanding of the intramembrane cleavage of the βCTF by γ-secretase, which may contribute to the future goal of developing an efficient therapeutic strategy for Alzheimer's disease. Frontiers Media S.A. 2014-11-27 /pmc/articles/PMC4245903/ /pubmed/25505888 http://dx.doi.org/10.3389/fphys.2014.00463 Text en Copyright © 2014 Morishima-Kawashima. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
Morishima-Kawashima, Maho
Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title_full Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title_fullStr Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title_full_unstemmed Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title_short Molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
title_sort molecular mechanism of the intramembrane cleavage of the β-carboxyl terminal fragment of amyloid precursor protein by γ-secretase
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245903/
https://www.ncbi.nlm.nih.gov/pubmed/25505888
http://dx.doi.org/10.3389/fphys.2014.00463
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