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Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence

The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Her...

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Autores principales: Chu, Jin, Li, Jian-Guo, Hoffman, Nicholas E., Stough, Alexandra M., Madesh, Muniswamy, Praticò, Domenico
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468577/
https://www.ncbi.nlm.nih.gov/pubmed/26076991
http://dx.doi.org/10.1038/srep11086
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author Chu, Jin
Li, Jian-Guo
Hoffman, Nicholas E.
Stough, Alexandra M.
Madesh, Muniswamy
Praticò, Domenico
author_facet Chu, Jin
Li, Jian-Guo
Hoffman, Nicholas E.
Stough, Alexandra M.
Madesh, Muniswamy
Praticò, Domenico
author_sort Chu, Jin
collection PubMed
description The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer’s disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer’s disease.
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spelling pubmed-44685772015-06-18 Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence Chu, Jin Li, Jian-Guo Hoffman, Nicholas E. Stough, Alexandra M. Madesh, Muniswamy Praticò, Domenico Sci Rep Article The formation of Aβ is directly controlled by the γ-secretase complex and its activator, γ-secretase activating protein (GSAP). GSAP derives from a C-terminal fragment of a larger precursor protein via a caspase-3 mediated cleavage. However, the mechanism regulating this process remains unknown. Here we provide in vitro experimental evidence that 5-Lipoxygenase (5LO) is as an endogenous regulator for GSAP formation, but not for other known γ-secretase modulators, by directly and specifically activating caspase-3. These results were confirmed in vivo by using transgenic mouse models of Alzheimer’s disease in which 5LO level and activity were modulated genetically or pharmacologically. Taken together, our findings demonstrate that GSAP cleavage via caspase-3 is regulated and depend upon the availability of 5LO further establishing this protein as an attractive and viable therapeutic target for Alzheimer’s disease. Nature Publishing Group 2015-06-16 /pmc/articles/PMC4468577/ /pubmed/26076991 http://dx.doi.org/10.1038/srep11086 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Chu, Jin
Li, Jian-Guo
Hoffman, Nicholas E.
Stough, Alexandra M.
Madesh, Muniswamy
Praticò, Domenico
Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title_full Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title_fullStr Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title_full_unstemmed Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title_short Regulation of gamma-secretase activating protein by the 5Lipoxygenase: in vitro and in vivo evidence
title_sort regulation of gamma-secretase activating protein by the 5lipoxygenase: in vitro and in vivo evidence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468577/
https://www.ncbi.nlm.nih.gov/pubmed/26076991
http://dx.doi.org/10.1038/srep11086
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