Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1782376522061971456 |
---|---|
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. |
format | Online Article Text |
id | pubmed-4468577 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT chujin regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence AT lijianguo regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence AT hoffmannicholase regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence AT stoughalexandram regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence AT madeshmuniswamy regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence AT praticodomenico regulationofgammasecretaseactivatingproteinbythe5lipoxygenaseinvitroandinvivoevidence |